Benzofuran potassium channel blockers and uses thereof

ABSTRACT

The present invention relates to compounds useful in the modulation of potassium channel activity in cells, in particular the activity of K v 1.3 channels found in T cells. The invention also relates to the use of these compounds in the treatment or prevention of autoimmune and inflammatory diseases, including multiple sclerosis, pharmaceutical compositions containing these compounds and methods for their preparation.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.60/849,488 filed on Oct. 4, 2006.

FIELD OF THE INVENTION

The present invention relates to compounds useful in the modulation ofpotassium channel activity in cells, in particular the activity of Kv1.3channels found in T cells. The invention also relates to the use ofthese compounds in the treatment or prevention of autoimmune andinflammatory diseases, including multiple sclerosis, pharmaceuticalcompositions containing these compounds and methods for theirpreparation.

BACKGROUND

Many autoimmune and chronic inflammatory diseases are related toimmunoregulatory abnormalities. Diseases such as systemic lupuserythematosis, chronic rheumatoid arthritis, multiple sclerosis andpsoriasis have in common the appearance of autoantibodies andself-reactive lymphocytes.

Multiple sclerosis is the most common neurological disease of youngpeople. It is believed to cost more in medical care and lost income thanany other neurological disease of young adults.

Multiple sclerosis affects the myelin sheaths of nerves. Myelin is aninsulating material that coats most axons and allows rapid signalconduction over long distances by saltatory conduction. It is thoughtthat antibodies and specialised cells of the immune system attack themyelin coating. This process leads to inflammation and scarring(sclerosis) which damages blood vessels in the area by the formation ofa lesion known as a plaque. These plaques are characterised by beinginfiltrated by macrophages and T cells. This results in demyelinationwith the consequential loss of the rapid signal conduction.

A possible method of treating these autoimmune and inflammatory diseasesis by suppressing T-cell proliferation and modulating their activation.

The early stages of T-cell activation may be conceptually separated intopre-Ca²⁺ and post-Ca²⁺ events (Cahalan and Chandy 1997, Curr. Opin.Biotechnol. 8 749). Following engagement of the T-cell receptor by anantigen, activation of tyrosine kinases and the generation of inositol1,4,5-triphosphate lead to the influx of Ca²⁺ and a rise in thecytoplasmic Ca²⁺ concentration. The rise in Ca²⁺ activates thephosphatase calcineurin, which then dephosphorylates a cytoplasmicallylocalized transcription factor (N-FAT) enabling it to accumulate in thenucleus and bind to a promoter element of the interleukin-2 gene. Alongwith parallel events involving the activation of protein kinase C andras, gene transcription leads to lymphokine secretion and to lymphocyteproliferation. Some genes require long-lasting Ca²⁺ signals while othersrequire only a transient rise of Ca²⁺.

Ion channels underlie the Ca²⁺ signal of T-lymphocytes. Ca²⁺ ions moveacross the plasma membrane through a channel termed the store-operatedCa²⁺ channel or the calcium release-activated Ca²⁺ channel. Two distincttypes of potassium channels indirectly determine the driving force ofcalcium entry. The first is the voltage-gated Kv1.3 channel (Cahalan1985, J. Physiol. 385: 197; Grissmer 1990, Proc. Natl. Acad. Sci. USA 879411; Verheugen 1995, J. Gen. Physiol. 105 765; Aiyar 1996, J. Biol.Chem. 271 31013; Cahalan and Chandy 1997, Curr. Opin. Biotechnol. 8 749)and the second is the intermediate-conductance calcium-activatedpotassium channel, IKCa1 (Grissmer 1993, J. Gen. Physiol. 102 601;Fanger 1999 J. Biol. Chem. 274 5746; Rauer 1999, J. Biol. Chem. 27421885; VanDorpe 1998, J. Biol. Chem. 273 21542; Joiner 1997, Proc. Natl.Acad. Sci. USA 94 11013; Khanna 1999, J. Biol. Chem. 274 14838; Lodgson1997, J. Biol. Chem. 272 32723; Ghanshani 1998, Genomics 51 160). Whenthese potassium channels open, the resulting efflux of K⁺ hyperpolarizesthe membrane, which in turn accentuates the entry of Ca²⁺, which isabsolutely required for downstream activation events (Cahalan and Chandy1997, Curr. Opin. Biotechnol. 8: 749).

The predominant voltage-gated channel in human T-lymphocytes is encodedby Kv1.3, a Shaker-related gene. Kv1.3 has been characterisedextensively at the molecular and physiological level and plays a vitalrole in controlling T-lymphocyte proliferation, mainly by maintainingthe resting membrane potential of resting T-lymphocytes. Inhibition ofthis channel depolarizes the cell membrane sufficiently to decrease theinflux of Ca²⁺ and thereby prevents downstream activation events.Advantageously the Kv1.3 channel is almost exclusively located inT-lymphocytes.

Accordingly, compounds which are selective Kv1.3 blockers are potentialtherapeutic agents as immunosuppressants for the prevention of graftrejection, and the treatment of autoimmune and inflammatory disorders.They could be used alone or in conjunction with otherimmunosuppressants, such as selective IKCa1 blockers or cyclosporin, inorder to achieve synergism and/or to reduce toxicity, especially ofcyclosporin.

Developments in the field of voltage-gated K-channel electrophysiologyhave strengthened the case for treating of multiple sclerosis and alsodiabetes mellitus by inhibiting the Kv1.3 channel. It was found thatautoreactive T-cells from multiple sclerosis patients exhibit highlyelevated levels of Kv1.3 (Wulff, H et al (2003) J. Clin Invest. 111 (11)1703-1713). ShK-K22Dap, a selective peptide blocker of Kv1.3, potentlyinhibited the proliferation of T-cells with this high-Kv1.3 phenotype.(Beeton, C. et al (2001) PNAS 98 13942-13947). The connection betweenT-cell replication and Kv1.3 blockade has also been shown through theuse of a small molecule, a psoralen derivative, that is an active andrelatively specific inhibitor of the Kv1.3 channel. The derivativeshowed specificity in inhibiting the proliferation of the high Kv1.3T-cells over peripheral blood T-cells (Vennekamp et al (2004) Mol.Pharm. 65 1364-1374).

The Kv1.3 channel has also been associated with diabetes. Studies ofKv1.3 knockout mice found that the mice have increased insulinsensitivity. The selective blockage of the Kv1.3 channel also led toincreased insulin sensitivity (Xu, J. et al. (2004) PNAS 101 (9),3122-3117). It has been suggested by Wulff, who was involved in theelectrophysiology on multiple sclerosis that diabetes also involvesautoreactive T-cells that express very high levels of Kv1.3 (Wulff, H.et al. (2003) Curr. Op.DDD. 6 640-647).

At present there exist a number of non-selective potassium channelblockers that will inhibit lymphocyte proliferation, but have adverseside effects. Other potassium channels exist in a wide range of tissuesincluding the heart and brain, and generally blocking these channels isundesirable. Accordingly it would be advantageous to provide or identifycompounds, which are selective inhibitors of the Kv1.3 channel.

U.S. Pat. No. 5,494,895 discloses the use of a thirty-nine amino acidpeptide, scorpion peptide margatoxin, as a selective inhibitor and probeof Kv1.3 channels present in human lymphocytes, and also as animmunosuppressant. However the use of this compound is limited by itspotent toxicity.

International Patent Application publication No's WO 97/16438 and WO09/716,437, and U.S. Pat. No. 6,051,590 describe the use of thetriterpene, correolide and related compounds as immunosuppressants. Thepotential for these compounds to become immunosuppressants wasillustrated by experiments showing their attenuation of the delayed-typehypersensitivity (DTH) response in mini-swine.

U.S. Pat. No. 6,077,680 describes DNA segments and proteins derived fromsea anemone species, more particularly ShK toxin from Stichodactylahelianthus. The ShK toxin was found to block Kv1.1, Kv1.3, Kv1.4 andKv1.6, but a mutant ShK-K22DAP was found to selectively block Kv1.3.Unfortunately the mutant did not exhibit the requisite pharmacokineticprofile for clinical use. A recently reported ShK analog, ShK(L5), wasat least 100-fold more active against Kv1.3 (K_(d)=69 pM) than Kv1.1 andfurthermore it showed at least 250-fold selectivity over every otherrelevant member of the Kv1 family (Beeton at al. (2005) Mol. Pharm. Inpress).

Both ShK toxin and ShK(L5) were shown to both prevent and treatexperimental autoimmune encephalomyelitis in Lewis rats, an animal modelfor human multiple sclerosis (Beeton, et al. (2001) Proc. Natl. Acad.Sci. USA 98 13942), by selectively targeting T-cells chronicallyactivated by the myelin antigen, MBP (myelin basic protein). The samestudy also indicated that chronically activated encephalitogenic ratT-cells express a unique channel phenotype characterised by highexpression of Kv1.3 channels (approximately 1500 per cell) and lownumbers of IKCa1 channels (approximately 120 per cell). This channelphenotype is distinct from that seen in quiescent and acutely activatedcells and may be a functionally relevant marker for chronicallyactivated rat T lymphocytes.

Other compounds which are blockers of Kv1.3 include psoralens (Vennekampet al. (2004) Mol. Pharm. 65, 1365-1374 and Wulff et al., US2006/0079535) and selected benzamides (Schalhofer et al. (2002) Biochem.41, 7781-7794 and Schalhofer et al (2003) Biochem. 42, 4733-4743.

Khellinone, a substituted benzofuran and natural product from certainplants, and 8-Methoxypsoralen (8-MOP), both commercially availableproducts, have been found to exhibit blocking activity on the Kv1.3channel.

Khellinone, 8-MOP and four dimeric variants thereof were described in aPoster (abstract. No. 1078) at a meeting of the American PhysiologicalSociety in Snowmass, Colo. (The Physiologist 42: A12 (1999)). Theauthors were testing whether linking two active units with a spacer,improved activity. Some of the bivalent derivatives were said to beineffective, and others were said to block the Kv1.3 channel, but lacktherapeutic utility due to their extreme sensitivity to hydrolysis (verypoor stability) and high lipophilicity (poor solubility in clinicalconditions).

European Patent Application 82201051 describes furano-chromonederivatives for use as anti-inflammatory agents amongst other suggesteduses. An intermediate compound used in the manufacture of the chromonederivatives was 5-(benzoylacetyl)-4,7-dimethoxy-6-hydroxy-benzofuran.

European Patent Application 83302551 describes a process for preparingdi-4,7-loweralkoxybenzofurans for use as intermediates in thepreparation of khellin and related compounds.

German patent DE 3710469 and European patent publication number EP303920describe the synthesis of5-acetyl-4-benzyloxy-7-methoxy-6-hydroxy-benzofuran by alkaline ringcleavage of a pyrone ring of a fused system. This is also described inan article by Musante in Annali de Chimica (1959) 46, 768-781 togetherwith the compound where the benzyloxy group is replaced with the residueof 2-hydroxyacetophenone.

An article by Bougery, G et al in J. Med. Chem. (1981) 24, 159-167described 4-alkoxy (ethoxy and iso-propoxy) khellinone derivatives foruse as intermediates in the manufacture of other compounds.

An article by Musante, C and Fatutta, S in Farmaco Eduzione Scientifics(1961) 16, 343-350 described a 7-glucosyl-khellinone compound for use asa coronary dilator.

Articles by Abdel Hafez, O et al in Molecules (online computer file)(2001), 6(4), 396-405, by El-Hafez, O, in Bulletin of the Faculty ofPharmacy (Cairo University) (1996), 34(2), 111-117 and by Ragab, F. A.and Tawfeek, H in Eur. J. Med. Chem. (1987) 22(3), 265-267 describeassorted khellinone derivatives with assorted alkylamines at the 7position.

SUMMARY OF THE INVENTION

The invention provides compounds of formula (I) or salts thereof,

wherein

is an optional double bond;R₁ and R₂ are independently selected from hydrogen, halo, optionallysubstituted lower alkyl, optionally substituted aryl, —OR, —C(O)R,—C(O)OR, —OC(O)R (where R is selected from hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted C₃₋₇ cycloalkyl, optionallysubstituted heterocyclyl, optionally substituted heteroaryl, andoptionally substituted aryl), —C(O)NR′R″, —NR′C(O)R″ and —NR′R″ (whereR′ and R″ are independently selected from hydrogen or lower alkyl);R₃ and R₄ are independently selected from hydrogen, cyano, halo, nitro,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted aryl, optionally substituted alkynyl, optionally substitutedC₃₋₇ cycloalkyl, optionally substituted C₄₋₇ cycloalkenyl, —OR, —C(O)R,—C(O)OR, —OC(O)R (where R is selected from hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted C₃₋₇ cycloalkyl, optionallysubstituted heterocyclyl, optionally substituted heteroaryl, andoptionally substituted aryl), —C(O)NR′R″, —NR′C(O)R″ and —NR′R″ (whereR′ and R″ are independently selected from hydrogen or lower alkyl);R₅ is selected from optionally substituted alkyl, —OR, —C(O)R, —C(O)OR,—OC(O)R, SR, (where R is selected from hydrogen, optionally substitutedalkyl, optionally substituted alkenyl, optionally substituted alkynyl,optionally substituted C₃₋₇ cycloalkyl, optionally substitutedheterocyclyl, optionally substituted heteroaryl, and optionallysubstituted aryl), —C(O)NR′R″, —NR′C(O)R″ and —NR′R″ (where R′ and R″are independently selected from hydrogen or lower alkyl);L is a divalent linker group of 1-6 atoms in length selected fromoptionally substituted alkylene, optionally substituted alkenylene,optionally substituted alkynylene; andR₆ is selected from halo, CN, optionally substituted C₃₋₇ cycloalkyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted heterocyclyl, —C(O)-heterocyclyl, —C(O)NR′″R′″,—NR′″R′″, —OR′″, SR′″, —S(O)R′″, —S(O)₂R′″, —Se(O)R′″, and Se(O)₂R′″(where each R′″ is independently selected from hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted C₃₋₇ cycloalkyl, optionallysubstituted heterocyclyl, optionally substituted heteroaryl, andoptionally substituted aryl).

In an aspect of the invention there is provided a method for thetreatment or prevention of autoimmune or chronic inflammatory diseases,or the prevention of rejection of foreign organ transplants and/orrelated afflictions, by the administration of a compound of formula I ora pharmaceutically acceptable salt thereof, or a composition containinga compound of formula I or pharmaceutically acceptable salt thereof.

In another aspect the invention provides the use of a compound offormula I or a salt thereof in the manufacture of a medicament for thetreatment or prevention of autoimmune or chronic inflammatory diseases,or the prevention of rejection of foreign organ transplants and/orrelated afflictions.

In another aspect of the invention there is provided a method ofintentionally modulating potassium ion channel activity of T-cells bythe application of a compound of Formula I, or a pharmaceuticallyacceptable salt thereof, to said T-cells.

In a further aspect of the invention there is provided a pharmaceuticalcomposition for use as an immunosuppressant, the composition comprisingan effective amount of a compound of Formula I or pharmaceuticallyacceptable salt thereof and optionally a carrier or diluent.

In another aspect of the invention there is provided a process for thepreparation of compounds of formula I or salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

The invention is based on the discovery that compounds of the generalformula I, as described in the above Summary of the Invention can haveuseful properties as inhibitors of potassium cell channels, andparticularly the Kv1.3 channel. Such compounds have significantpotential as immunosuppressants for the treatment of autoimmunedisorders such as multiple sclerosis and rheumatoid arthritis. They mayalso be useful in the treatment or prevention of graft rejection.

The term “alkyl” as used alone or in combination herein refers to astraight or branched chain saturated hydrocarbon group. The term “C₁₋₁₂alkyl” refers to such a group containing from one to twelve carbon atomsand the terms “C₁₋₆ alkyl” and “lower alkyl” refer to such groupscontaining from one to six carbon atoms, such as methyl (“Me”), ethyl(“Et”), n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyland the like.

The term “alkylene” refers to divalent alkyl groups preferably havingfrom 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms.Examples of such alkylene groups include methylene (—CH₂—), ethylene(—CH₂CH₂—), and the propylene isomers (e.g., —CH₂CH₂CH₂— andCH(CH₃)CH₂—), and the like.

The term “C₃₋₇ cycloalkyl” refers to non-aromatic, saturatednon-aromatic carbocycles having from 3 to 7 carbon atoms. Examplesinclude cyclopentyl and cyclohexyl.

The term “alkenyl” refers to a straight or branched hydrocarboncontaining one or more double bonds, preferably one or two double bonds.The term “C₂₋₁₂ alkenyl” refers to such a group containing from two totwelve carbon atoms. Examples of alkenyl include allyl, 1-methylvinyl,butenyl, iso-butenyl, 1,3-butadienyl, 3-methyl-2-butenyl,1,3-butadienyl, 1,4-pentadienyl, 1-pentenyl, 1-hexenyl, 3-hexenyl,1,3-hexadienyl, 1,4-hexadienyl and 1,3,5-hexatrienyl.

The term “alkenylene” refers to divalent alkenyl groups preferablyhaving from 2 to 8 carbon atoms and more preferably 2 to 6 carbon atoms.Examples include ethenylene (—CH═CH—), and the propenylene isomers(e.g., —CH₂CH═CH— and —C(CH₃)═CH—), and the like.

The term “C₄₋₇ cycloalkenyl” refers to non aromatic carbocycles having 4to 7 carbon atoms and having one or more double bonds. Examples includecyclopentenyl, 1-methyl-cyclopentenyl, cyclohexenyl,1,3-cyclopentadienyl, 1,3-cyclohexadienyl and 1,4-cyclohexadienyl.

The term “alkynyl” refers to a straight or branched hydrocarboncontaining one or more triple bonds, preferably one or two triple bonds.The term “C₂₋₁₂ alkynyl” refers to such a group containing from two totwelve carbon atoms. Examples include 2-propynyl and 2- or 3-butynyl.

The term “alkynylene” refers to the divalent alkynyl groups preferablyhaving from 2 to 8 carbon atoms and more preferably 2 to 6 carbon atoms.Examples include ethynylene (—C≡C—), propynylene (—CH₂—C≡C—), and thelike.

The term “alkoxy” as used alone or in combination refers to a straightor branched chain alkyl group covalently bound via an oxygen linkage(—O—) and the terms “C₁₋₆ alkoxy” and “lower alkoxy” refer to suchgroups containing from one to six carbon atoms, such as methoxy, ethoxy,propoxy, isopropoxy, butoxy, t-butoxy and the like.

The terms “alkenyloxy” and “alkynyloxy” as used alone or in combinationrespectively refer to an alkenyl and alkynyl group as earlier describedlinked via an oxygen linkage (—O—).

The term “aromatic” when used alone or in combination refers tomonocyclic or bicyclic aryl rings and ring systems (aromatic hydrocarbonrings or ring systems) and also aromatic heterocyclic rings or ringsystems, as known as heteroaryl or heteroaromatic rings. Preferredaromatic rings are optionally substituted phenyl (“Ph”) rings.

The term “aryl” refers to carbocyclic (non-heterocyclic) aromatic ringsor ring systems. The aromatic rings may be mono- or bi-cyclic ringsystems. The aromatic rings or ring systems are generally composed of 5to 10 carbon atoms. Examples of suitable aryl groups include but are notlimited to phenyl, biphenyl, naphthyl, tetrahydronaphthyl, and the like.

Preferred aryl groups include phenyl, naphthyl, indenyl, azulenyl,fluorenyl or anthracenyl.

The term “heteroaryl” refers to a monovalent aromatic carbocyclic group,preferably of from 2 to 10 carbon atoms and 1 to 4 heteroatoms selectedfrom oxygen, nitrogen and sulfur within the ring. Preferably theheteroatom is nitrogen. Such heteroaryl groups can have a single ring(e.g., pyridyl, pyrrolyl or furyl) or multiple condensed rings (e.g.,indolizinyl or benzothienyl).

The term “heterocyclyl” refers to a monovalent saturated or unsaturatedgroup having a single ring or multiple condensed rings, preferably from1 to 8 carbon atoms and from 1 to 4 hetero atoms selected from nitrogen,sulfur, oxygen, selenium or phosphorous within the ring.

Examples of 5-membered monocyclic heterocyclyl and heteroaryl groupsinclude furyl, thienyl, pyrrolyl, H-pyrrolyl, pyrrolinyl, pyrrolidinyl,oxazolyl, oxadiazolyl, (including 1,2,3 and 1,2,4 oxadiazolyls)thiazolyl, isoxazolyl, furazanyl, isothiazolyl, pyrazolyl, pyrazolinyl,pyrazolidinyl, imidazolyl, imidazolinyl, triazolyl (including 1,2,3 and1,3,4 triazolyls), tetrazolyl, thiadiazolyl (including 1,2,3 and 1,3,4thiadiazolyls).

Examples of 6-membered monocyclic heterocyclyl and heteroaryl groupsinclude pyridyl, pyrimidinyl, pyridazinyl, pyranyl, pyrazinyl,piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl,piperazinyl, 1,3,5-trithianyl and triazinyl.

The above heterocycles may be optionally substituted with a broad rangeof substituents, such as C₁₋₆ alkyl, C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₂₋₆alkynyl, halo, hydroxy, mercapto, trifluoromethyl, phenyl, phenyloxy,phenylalkyl, phenylalkyloxy, amino, cyano or mono or di(C₁₋₆alkyl)amino.

As referred to above heterocycle or heteroaryl may be fused to acarbocyclic ring such as phenyl, naphthyl, indenyl, azulenyl, fluorenyl,and anthracenyl.

Examples of 8, 9 and 10-membered bicyclic heterocyclyl and heteroarylgroups include 1H thieno[2,3-c]pyrazolyl, thieno[2,3-b]furyl, indolyl,isoindolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl,benzisoxazolyl, benzisothiazolyl, benzimidazolyl, indazolyl,isoquinolinyl, quinolinyl, quinoxalinyl, uridinyl, purinyl, cinnolinyl,phthalazinyl, quinazolinyl, quinoxalinyl, benzotriazinyl,naphthyridinyl, pteridinyl and the like. These heterocycles may beoptionally substituted, for example with C₁₋₆alkyl, C₁₋₆alkoxy,C₂₋₆alkenyl, C₂₋₆alkynyl, halo, hydroxy, mercapto, trifluoromethyl,cyano, phenyl, phenyloxy, phenylalkyl, phenylalkyloxy, amino and mono ordi(C₁₋₆alkyl)amino.

Examples of some preferred heterocyclic and heteroaromatic radicalsinclude (optionally substituted) isoxazoles, isothiazoles,1,3,4-oxadiazoles, 1,3,4-thiadiazoles, 1,2,4-oxadiazoles,1,2,4-thiadiazoles, oxazoles, thiazoles, pyridines, pyridazines,pyrimidines, pyrazines, 1,2,4-triazines, 1,3,5-triazines, benzoxazoles,benzothiazoles, benzisoxazoles, benzisothiazoles, quinolines,quinoxalines, furyl, thienyl, pyridyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,4-oxadiazol-5-one, 1,2,3-triazolyl,1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl,1,3,5-triazinyl, 1H thieno[2,3-c]pyrazolyl, thieno[2,3-b]furyl,indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl,benzo[b]furanyl, benzo[b]thiophenyl, 1H-indazolyl, benzimidazolyl,tetrazolyl, uridinyl, and cytosinyl. These radicals can be optionallysubstituted with, by example, C₁₋₆alkyl, C₁₋₆alkoxy, C₂₋₆alkenyl,C₂₋₆alkynyl, halo, hydroxy, mercapto, trifluoromethyl, amino, phenyl,phenyloxy, phenylalkyl, phenylalkyloxy, cyano or mono ordi(C₁₋₆alkyl)amino.

Heteroaryl or heteroaromatic rings may preferably be selected fromisoxazolyl, oxazolyl, imidazolyl, thiazolyl, thiadiazolyl, isothiazolyl,furazanyl, triazolyl, pyridyl, pyrimidinyl, furyl, pyrazolyl,pyridazinyl, thienyl and aryl fused heteroaromatic rings such asbenzfuranyl, benzothiophenyl and benzoisoxazolyl.

Heterocyclyl or heterocyclic rings may preferably be selected frompyrrolidine, imidazoline, 2-imidazolidone, 2-pyrrolidone,pyrrolin-2-one, tetrahydrofuran, 1,3-dioxolane, piperidine,tetrahydropyran, oxazoline, 1,3-dioxane, 1,4-piperazine, morpholine andthiomorpholine.

The term “arylalkyl” refers to carbocyclic aromatic rings or ringsystems as previously described and substituted by an alkyl group, alsoas previously described. Unless otherwise indicated the aryl substituentis attached by the alkyl part of the substituent. Likewise the terms“aryl C₁₋₁₂ alkyl”, “aryl C₂₋₁₂ alkenyl” and “aryl C₂₋₁₂ alkynyl” referto carbocyclic aromatic rings or ring systems as previously describedand substituted by a C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl or C₂₋₁₂ alkynyl group,as previously described.

The terms “halo” and “halogen” refers to fluoro, chloro, bromo and iodogroups.

The term “halo alkyl” group has one or more of the hydrogen atoms on analkyl group replaced with halogens. A notable example is —CF₃.

The term “aryloxy” refers to an aryl group as earlier described linkedto the parent structure via an oxygen linkage (—O—). A notable exampleis phenoxy. Similarly the term “heteroaryloxy” refers to a heteroarylgroup as earlier described linked to the parent structure via an oxygengroup. A notable example is a 4, 6 or 7-benzo[b]furanyloxy group.

“Divalent linker group” is taken to mean a divalent group capable offorming a stable bridge between the core structure of formula (I) orformula (Ia) and the radical R₆. Examples of divalent linker groupsinclude alkylene, alkenylene, alkynylene, arylene, heteroarylene,heterocyclylene, alkylenearylene, alkylenearylenealkylene,alkyleneheteroarylenealkylene, alkyleneheterocyclylenealkylene, and thelike.

The term “optionally substituted” means that a group may include one ormore substituents. One or more hydrogen atoms on the group may bereplaced by substituent groups independently selected from halogens,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, —(CH₂)_(p)C₃₋₇ cycloalkyl,—(CH₂)_(p)C₄₋₇ cycloalkenyl, —(CH₂)_(p) aryl, —(CH₂)_(p) heterocyclyl,—(CH₂)_(p) heteroaryl, —C₆H₄S(O)_(q)C₁₋₆ alkyl, C(Ph)₃, —CN, —OR,—O—-(CH₂)₁₋₆—R, —O—(CH₂)₁₋₆—OR, —OC(O), —C(O), —C(O)OR, —OC(O)NR′R″,NR′R″, —NRC(O)R′, —NRC(O)NR′R″, —NRC(S)NR′R″, —NRS(O)₂R′, —NRC(O)OR′,—C(NR)NR′R″, —C(═NOR′), —C(═NOH)NR′R″, —C(O)NR′R″, —C(═NCN)—NR′R″,—C(═NR)NR′R″, —C(═NR′)SR″, —NR′C(═NCN)SR″, —CONRSO₂R′, —C(S)NR′R″,—S(O)_(q)R, —SO₂NR′R″, —SO₂NRC(O)R′, —OS(O)₂R, —PO(OR)₂ and —NO₂;

where p is 0-6, q is 0-2 and each R, R′ and R″ is independently selectedfrom H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, C₄₋₇cycloalkenyl, aryl, heterocyclyl, heteroaryl, C₁₋₆ alkylaryl, C₁₋₆alkylheteroaryl, and C₁₋₆ alkylheterocyclyl, wherein the alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl, heteroaryl, C₁₋₆alkylaryl, C₁₋₆ alkylheteroaryl, or C₁₋₆ alkylheterocyclyl, may beoptionally substituted with one to six of same or different groupsselected from halogen, hydroxy, lower alkyl, lower alkoxy, —CO₂H, CF₃,CN, phenyl, NH₂ and NO₂; or when R′ and R″ are attached to the samenitrogen atom, they may, together with the atom to which they areattached, form a 5 to 7 membered nitrogen containing heterocyclic ring.

In the case of the divalent linker group, the term “optionallysubstituted” also indicates that one or more saturated carbon atoms maybe substituted for a heteroatom or heterogroup, such as O, S, NH and thelike. For example an optionally substituted alkylene group could berepresented by a group such as —CH₂CH₂OCH₂—, —CH₂—O—CH₂—,—CH₂CH₂OCH₂CH₂OCH₂CH₂—, —CH₂CH₂NH—CH₂—, —CH₂NHCH₂—, and the like.

Unless otherwise defined and only in respect of the ring atoms ofnon-aromatic carbocyclic or heterocyclic compounds, the ring atoms ofsuch compounds may also be optionally substituted with one or two ═Ogroups, instead of or in addition to the above described optionalsubstituents.

When the optional substituent is or contains an alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocyclyl group, thegroup may itself be optionally substituted with one to six of the sameor different substituents selected from halogens, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ haloalkyl (in particular —CF₃), C₁₋₆haloalkoxy (such as —OCF₃), —OH, phenyl, benzyl, phenoxy, benzyloxy,benzoyl, —NH₂, —NHC₁₋₄ alkyl, —N(C₁₋₄ alkyl)₂, —CN, —NO₂, mercapto, C₁₋₆alkylcarbonyl, C₁₋₆ alkoxycarbonyl and CO₂H.

The salts of the compound of formula I are preferably pharmaceuticallyacceptable, but it will be appreciated that non-pharmaceuticallyacceptable salts also fall within the scope of the present invention,since these are useful as intermediates in the preparation ofpharmaceutically acceptable salts.

It will be appreciated that the compounds of formula I, and the saltsthereof, can be presented in the form of pharmaceutically acceptablederivatives. The term “pharmaceutically acceptable derivative” includespharmaceutically acceptable esters, prodrugs, solvates and hydrates ofthe compounds of formula I or salts thereof. Pharmaceutically acceptablederivatives may include any pharmaceutically acceptable hydrate or anyother compound or prodrug which, upon administration to a subject, iscapable of providing (directly or indirectly) a compound of formula I oran active metabolite or residue thereof.

The pharmaceutically acceptable salts include acid addition salts, baseaddition salts, and the salts of quaternary amines and pyridiniums. Theacid addition salts are formed from a compound of the invention and apharmaceutically acceptable inorganic or organic acid including but notlimited to hydrochloric, hydrobromic, sulfuric, phosphoric,methanesulfonic, toluenesulphonic, benzenesulphonic, acetic, propionic,ascorbic, citric, malonic, fumaric, maleic, lactic, salicylic, sulfamic,or tartaric acids. The counter ion of quaternary amines and pyridiniumsinclude chloride, bromide, iodide, sulfate, phosphate, methanesulfonate,citrate, acetate, malonate, fumarate, sulfamate, and tartrate. The baseaddition salts include but are not limited to salts such as sodium,potassium, calcium, lithium, magnesium, ammonium and alkylammonium.Also, basic nitrogen-containing groups may be quaternised with suchagents as lower alkyl halides, such as methyl, ethyl, propyl, and butylchlorides, bromides and iodides; dialkyl sulfates like dimethyl anddiethyl sulfate; and others. The salts may be made in a known manner,for example by treating the compound with an appropriate acid or base inthe presence of a suitable solvent.

The compounds of the invention may be in crystalline form or as solvates(e.g. hydrates) and it is intended that both forms be within the scopeof the present invention. The term “solvate” is a complex of variablestoichiometry formed by a solute (in this invention, a compound of theinvention) and a solvent. Such solvents should not interfere with thebiological activity of the solute. Solvents may be, by way of example,water, ethanol or acetic acid. Methods of solvation are generally knownwithin the art.

The term “pro-drug” is used in its broadest sense and encompasses thosederivatives that are converted in vivo to the compounds of theinvention. Such derivatives would readily occur to those skilled in theart, and include, for example, compounds where a free hydroxy group isconverted into an ester derivative or a ring nitrogen atom is convertedto an N-oxide. Examples of ester derivatives include alkyl esters,phosphate esters and those formed from amino acids, preferably valine.Any compound that is a prodrug of a compound of the invention is withinthe scope and spirit of the invention.

The term “pharmaceutically acceptable ester” includes biologicallyacceptable esters of compound of the invention such as sulphonic,phosphonic and carboxylic acid derivatives.

Thus, in another aspect of the invention, there is provided a prodrug orpharmaceutically acceptable ester of a compound of formula I of saltthereof.

It will be appreciated that the compounds of formula I and somederivatives thereof may have at least one asymmetric centre, andtherefore are capable of existing in more than one stereoisomeric form.The invention extends to each of these forms individually and tomixtures thereof, including racemates. The isomers may be separatedconventionally by chromatographic methods or using a resolving agent.Alternatively the individual isomers may be prepared by asymmetricsynthesis using chiral intermediates. Where the compound has at leastone carbon-carbon double bond, it may occur in Z- and E-forms with allisomeric forms of the compounds being included in the present invention.

In some preferred embodiments of the invention, and with reference tothe general formula I, one or more of the following preferreddefinitions apply:

a) R₁ and R₂ are independently selected from hydrogen, lower alkyl orhalo, and are preferably hydrogen or one of R₁ and R₂ is halo(preferably chloro) and the other hydrogen.

b) R₅ is an optionally substituted C₁₋₆ alkyl for example, preferably—CH₂C(O) loweralkyl and CH₂C(O)O-loweralkyl, more preferably anunsubstituted C₁₋₆ alkyl and most preferably methyl.

Preferably, R₁ and R₂ are both hydrogen and R₅ is methyl, or R₁ ischloro, R₂ is hydrogen and R₅ is methyl.

c) One of R₃ and R₄ is optionally substituted C₁₋₁₀ alkyl, optionallysubstituted C₂₋₁₀ alkenyl, optionally substituted C₂₋₁₀ alkynyl,optionally substituted C₁₋₁₀ alkoxy, optionally substituted C₂₋₁₀alkenyloxy, optionally substituted C₂₋₁₀ alkynyloxy. Preferably it ishydrogen, optionally substituted C₁₋₁₀ alkyl or optionally substitutedC₁₋₁₀ alkoxy. More preferably C₁₋₂ alkoxy or C₁₋₃ alkyl. Most preferablymethyl or methoxy.d) The other of R₃ and R₄ is a substituted C₁₋₁₀ alkyl, substitutedC₁₋₁₀ alkoxy group (preferably a lower alkyl or alkoxy group),substituted C₂₋₆ alkenyl, substituted C₂₋₆ alkenyloxy, substituted C₂₋₆alkynyl or substituted C₂₋₆ alkynyloxy. More preferably a substitutedmethyl/methoxy, substituted ethyl/ethoxy, substituted propyl/propyloxy,substituted ethenyl/ethenyloxy, substituted propenyl/propenyloxy,substituted ethynyl/ethynyloxy, or substituted propynyl/propynyloxygroup. In an embodiment the aforementioned groups are terminallysubstituted. Preferred substituents include optionally substituted aryl,optionally substituted aryloxy, optionally substituted heteroaryl,optionally substituted heteroaryloxy, optionally substitutedheterocyclyl, optionally substituted heterocyclyloxy, and NR′R″ where R′and R″ independently represents hydrogen and lower alkyl.

Preferably R₃ is selected from the groups listed in c) and R₄ isselected from the groups listed in d).

Accordingly, in a preferred embodiment the present invention providescompounds of formula (Ia) or salts thereof,

wherein

is an optional double bond;R₁ is chloro or hydrogen;R₂ is hydrogen;R₃ is methyl or methoxy;R₄ is selected from lower alkyl, lower alkoxy, C₂₋₆ alkenyl, C₂₋₆alkenyloxy, C₂₋₆ alkynyl, or C₂₋₆ alkynyloxy, each substituted byoptionally substituted aryl, optionally substituted aryloxy, optionallysubstituted heteroaryl, optionally substituted heteroaryloxy, optionallysubstituted heterocyclyl, optionally substituted heterocyclyloxy, orNR′R″ (where R′ and R″ are independently selected from hydrogen andlower alkyl);L is a divalent linker group of 1-6 atoms in length selected fromoptionally substituted alkylene, optionally substituted alkenylene,optionally substituted alkynylene; andR₆ is selected from halo, CN, optionally substituted C₃₋₇ cycloalkyl,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted heterocyclyl, —C(O)-heterocyclyl, —C(O)NR′″R′″,—NR′″R′″, —OR′″, —SR′″, —S(O)R′″, —S(O)₂R′″, —Se(0)R′″, and —Se(O)₂R′″(where each R′″ is independently selected from hydrogen, optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted C₃₋₇ cycloalkyl, optionallysubstituted heterocyclyl, optionally substituted heteroaryl, andoptionally substituted aryl).

In other preferred embodiments of the invention, and with reference tothe general formulae I and Ia, one or more of the following preferreddefinitions apply:

e) L is an optionally substituted alkylene (including for instancepreferably CH₂OCH₂— and CH₂CH₂OCH₂CH₂—) and more preferably anunsubstituted alkylene group. Also, preferably L is a divalent linkergroup of from 2-4 atoms in length. Thus, most preferably L is anunsubstituted ethylene, propylene, or butylene group.f) R₆ is halo, CN, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted heterocyclyl, —C(O)-heterocyclyl,—C(O)NR′″R′″, —NR′″R′″, —OR′″, —SR″, —S(O)R′″, —S(O)₂R′″, —Se(0)R′″, and—Se(O)₂R′″ (where R′″ is selected from optionally substituted alkyl,optionally substituted C₃₋₇ cycloalkyl, optionally substitutedheterocyclyl, optionally substituted heteroaryl and optionallysubstituted aryl). More preferably R₆ is CN, optionally substitutedaryl, optionally substituted heteroaryl, optionally substitutedheterocyclyl, —C(O)-heterocyclyl, —C(O)NR′″R′″, —NR′″R′″, —OR′″, —SR′″,—S(O)R′″, or —S(O)₂R′″ (where each R′″ is independently selected fromoptionally substituted alkyl, optionally substituted C₃₋₇ cycloalkyl,optionally substituted heterocyclyl, optionally substituted heteroaryland optionally substituted aryl).

Accordingly, in an even more preferred embodiment the present inventionprovides compounds of formula (Ia) or salts thereof wherein

is a double bond;

R₃ is methyl or methoxy;

R₄ is a lower alkyl or lower alkoxy terminally substituted by optionallysubstituted aryl, optionally substituted aryloxy, optionally substitutedheteroaryl, optionally substituted heteroaryloxy, optionally substitutedheterocyclyl, optionally substituted heterocyclyloxy, or NR′R″ (where R′and R″ are independently selected from hydrogen and lower alkyl);L is a divalent linker group of 2-4 atoms in length selected from aethylene, propylene or butylene; andR₆ is CN, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted heterocyclyl, —C(O)-heterocyclyl,—C(O)NR′″R′″, —NR′″R′″, —OR′″, —SR′″, —S(O)R′″, or —S(O)₂R′″ (where R′″is selected from optionally substituted alkyl, optionally substitutedC₃₋₇ cycloalkyl, optionally substituted heterocyclyl, optionallysubstituted heteroaryl and optionally substituted aryl).

For the preferred groups listed in d) and f) above (in respect of R₃, R₄and R₆) the optionally substituted alkyl, optionally substituted aryl,optionally substituted cycloalkyl, optionally substituted heteroaryl,optionally substituted heterocyclyl groups may be substituted with from1 to 4 substituents. Preferably the substituents may be independentlyselected from fluoro, chloro, bromo, lower alkyl, lower haloalkyl, loweralkoxy, lower haloalkoxy, nitro, hydroxyl, carboxyl, phenyl, naphthyl,benzyl and benzoyl.

The invention also includes where possible a salt or pharmaceuticallyacceptable derivative such as a pharmaceutically acceptable ester,solvate and/or prodrug of the above mentioned embodiments of theinvention.

In another aspect of the invention, there is provided a pharmaceuticalcomposition that comprises a therapeutically effective amount of one ormore of the aforementioned compounds of formulae I/Ia orpharmaceutically acceptable salts thereof, including pharmaceuticallyacceptable derivatives thereof, and optionally a pharmaceuticallyacceptable carrier or diluent.

In another aspect, the present invention provides pharmaceuticalcompositions for use as a Kv1.3 ion channel blocker, more particularlyas an immunosuppressant, the composition comprising an effective amountof a compound of Formulae I/Ia or a pharmaceutically acceptable saltthereof, including a pharmaceutically acceptable derivative thereof, andoptionally a pharmaceutically acceptable carrier or diluent.

The term “composition” is intended to include the formulation of anactive ingredient with encapsulating material as carrier, to give acapsule in which the active ingredient (with or without other carrier)is surrounded by carriers.

The pharmaceutical compositions or formulations include those suitablefor oral, rectal, nasal, topical (including buccal and sub-lingual),vaginal or parenteral (including intramuscular, sub-cutaneous andintravenous) administration or in a form suitable for administration byinhalation or insufflation.

The compounds of the invention, together with a conventional adjuvant,carrier, or diluent, may thus be placed into the form of pharmaceuticalcompositions and unit dosages thereof, and in such form may be employedas solids, such as tablets or filled capsules, or liquids such assolutions, suspensions, emulsions, elixirs, or capsules filled with thesame, all for oral use, in the form of suppositories for rectaladministration; or in the form of sterile injectable solutions forparenteral (including subcutaneous) use.

Such pharmaceutical compositions and unit dosage forms thereof maycomprise conventional ingredients in conventional proportions, with orwithout additional active compounds or principles, and such unit dosageforms may contain any suitable effective amount of the active ingredientcommensurate with the intended daily dosage range to be employed.Formulations containing ten (10) milligrams of active ingredient or,more broadly, 0.1 to one hundred (100) milligrams, per tablet, areaccordingly suitable representative unit dosage forms.

The compounds of the present invention can be administered in a widevariety of oral and parenteral dosage forms. It will be obvious to thoseskilled in the art that the following dosage forms may comprise, as theactive component, either a compound of the invention or apharmaceutically acceptable salt of a compound of the invention.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispensable granules. Asolid carrier can be one or more substances which may also act asdiluents, flavouring agents, solubilisers, lubricants, suspendingagents, binders, preservatives, tablet disintegrating agents, or anencapsulating material.

In powders, the carrier is a finely divided solid that is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted in theshape and size desired.

The powders and tablets preferably contain from five or ten to aboutseventy percent of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as carrier providing acapsule in which the active component, with or without carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as an admixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized moulds, allowedto cool, and thereby to solidify.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or sprays containing inaddition to the active ingredient such carriers as are known in the artto be appropriate.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water-propylene glycol solutions. For example,parenteral injection liquid preparations can be formulated as solutionsin aqueous polyethylene glycol solution.

Sterile liquid form compositions include sterile solutions, suspensions,emulsions, syrups and elixirs. The active ingredient can be dissolved orsuspended in a pharmaceutically acceptable carrier, such as sterilewater, sterile organic solvent or a mixture of both.

The compounds according to the present invention may thus be formulatedfor parenteral administration (e.g. by injection, for example bolusinjection or continuous infusion) and may be presented in unit dose formin ampoules, pre-filled syringes, small volume infusion or in multi-dosecontainers with an added preservative. The compositions may take suchforms as suspensions, solutions, or emulsions in oily or aqueousvehicles, and may contain formulation agents such as suspending,stabilising and/or dispersing agents. Alternatively, the activeingredient may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilisation from solution, for constitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavours,stabilising and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, or other well known suspending agents.

Also included are solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavours, stabilisers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilising agents, andthe like.

For topical administration to the epidermis the compounds according tothe invention may be formulated as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also contain one or more emulsifying agents,stabilising agents, dispersing agents, suspending agents, thickeningagents, or colouring agents.

Formulations suitable for topical administration in the mouth includelozenges comprising active agent in a flavoured base, usually sucroseand acacia or tragacanth; pastilles comprising the active ingredient inan inert base such as gelatin and glycerin or sucrose and acacia; andmouthwashes comprising the active ingredient in a suitable liquidcarrier.

Solutions or suspensions are applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or spray. Theformulations may be provided in single or multidose form. In the lattercase of a dropper or pipette, this may be achieved by the patientadministering an appropriate, predetermined volume of the solution orsuspension. In the case of a spray, this may be achieved for example bymeans of a metering atomizing spray pump. To improve nasal delivery andretention the compounds according to the invention may be encapsulatedwith cyclodextrins, or formulated with other agents expected to enhancedelivery and retention in the nasal mucosa.

Administration to the respiratory tract may also be achieved by means ofan aerosol formulation in which the active ingredient is provided in apressurised pack with a suitable propellant such as a chlorofluorocarbon(CFC) for example dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, carbon dioxide, or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by provision of a metered valve.

Alternatively the active ingredients may be provided in the form of adry powder, for example a powder mix of the compound in a suitablepowder base such as lactose, starch, starch derivatives such ashydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).Conveniently the powder carrier will form a gel in the nasal cavity. Thepowder composition may be presented in unit dose form for example incapsules or cartridges of, e.g., gelatin, or blister packs from whichthe powder may be administered by means of an inhaler.

In formulations intended for administration to the respiratory tract,including intranasal formulations, the compound will generally have asmall particle size for example of the order of 5 to 10 microns or less.Such a particle size may be obtained by means known in the art, forexample by micronization.

When desired, formulations adapted to give sustained release of theactive ingredient may be employed.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

The invention also includes the compounds in the absence of carrierwhere the compounds are in unit dosage form.

The amount of compound of Formulae I/Ia administered may be in the rangefrom about 10 mg to 2000 mg per day, depending on the activity of thecompound and the disease to be treated.

Liquids or powders for intranasal administration, tablets or capsulesfor oral administration and liquids for intravenous administration arethe preferred compositions.

The compositions may further contain one or more other immunosuppressivecompounds. For example the compositions may contain a secondimmunosuppressive agent such as azathioprine, brequinar sodium,deoxyspergualin, mizoribine, mycophenolic acid morpholino ester,cyclosporin, FK-506 and rapamycin.

The compounds of the present invention may be useful in the therapeuticor prophylactic treatment of the resistance to transplantation of organsor tissue (such as heart, kidney, liver, lung, bone marrow, cornea,pancreas, intestinum tenue, limb, muscle, nervous, medulla ossium,duodenum, small-bowel, medulla ossium, skin, pancreatic islet-cell, etc.including xeno transplantation), graft-versus-host diseases; rheumatoidarthritis, systemic lupus erythematosus, nephrotic syndrome lupus,Palmo-planter pustulosis, Hashimoto's thyroiditis, multiple sclerosis,Guillain-Barre syndrome, myasthenia gravis, type I diabetes uveitis,juvenile-onset or recent-onset diabetes mellitus, diabetic neuropathy,posterior uveitis, allergic encephalomyelitis, glomerulonephritis,infectious diseases caused by pathogenic microorganisms, inflammatoryand hyperproliferative skin diseases, psoriasis, atopical dermatitis,contact dermatitis, eczematous dermatitises, seborrhoeis dermatitis,Lichen planus, Pemphigus, bullous pemphigoid, Epidermolysis bullosa,urticaria, angioedemas, vasculitides, erythemas, cutaneouseosinophilias, Lupus erythematosus, acne, Alopecia greata,keratoconjunctivitis, vernal conjunctivitis, uveitis associated withBehcet's disease, keratitis, herpetic keratitis, conical cornea,dystrophia epithelialis corneae, corneal leukoma, ocular pemphigus,Mooren's ulcer, Scleritis, Graves' opthalmopathy, Vogt-Koyanagi-Haradasyndrome, sarcoidosis, etc.; pollen allergies, reversible obstructiveairway disease, bronchial asthma, allergic asthma, intrinsic asthma,extrinsic asthma and dust asthma, chronic or inveterate asthma, lateasthma and airway hyper-responsiveness, bronchitis, gastric ulcers,vascular damage caused by ischemic diseases and thrombosis, ischemicbowel diseases, inflammatory bowel diseases, necrotizing enterocolitis,intestinal lesions associated with thermal burns and leukotrieneB₄-mediated diseases, Coeliac diseases, proctitis, eosinophilicgastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis,migraine, rhinitis, eczema, interstitial nephritis, Good-pasture'ssyndrome, hemolytic-uremic syndrome, diabetic nephropathy, multiplemyositis, Meniere's disease, polyneuritis, multiple neuritis,mononeuritis, radiculopathy, hyperthyroidism, Basedow's disease, purered cell aplasia, aplastic anaemia, hypoplastic anemia, idiopathicthrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis,pernicious anemia, megaloblastic anemia, anerythroplasia, osteoporosis,sarcoidosis, fibroid lung, idiopathic interstitial pneumonia,dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photoallergicsensitivity, cutaneous T-cell lymphoma, arteriosclerosis,atherosclerosis, aortitis syndrome, polyarteritis nodosa, myocardosis,scleroderma, Wegener's granuloma, adiposis, eosinophilic fascitis,lesions of gingiva, periodontium, alveolar bone, substantia osseadentis, glomerulonephritis, male pattern alopecia or alopecia senilis bypreventing epilation or providing hair germination and/or promoting hairgeneration and hair growth; muscular dystrophy; Pyoderma and Sezary'ssyndrome, Sjoegren's syndrome, Addison's disease, ischemia-reperfusioninjury of organs which occurs upon preservation, transplantation orischemic disease, for example, thrombosis and cardiac infarction,endotoxin-shock, pseudomembranous colitis, colitis caused by drug orradiation, ischemic acute renal insufficiency, chronic renalinsufficiency, toxinosis caused by lung-oxygen or drug, for example,paracort and bleomycins, lung cancer, pulmonary emphysema, cataracta,siderosis, retinitis, pigmentosa, senile macular degeneration, vitrealscarring, corneal alkali burn; dermatitis erythema multiforme, linearIgA ballous dermatitis and cement dermatitis, gingivitis, periodontitis,sepsis, pancreatitis, diseases caused by environmental pollution, aging,carcinogenis, metastasis of carcinoma and hypobaropathy; disease causedby histamine or leukotriene-C₄ release; Berger's disease, Behcet'sdisease, autoimmune hepatitis, primary biliary cirrhosis sclerosingcholangitis, partial liver resection, acute liver necrosis, necrosiscaused by toxin, viral hepatitis, shock, or anoxia, B-virus hepatitis,non-A/non-B hepatitis, cirrhosis, alcoholic cirrhosis, hepatic failure,fulminant hepatic failure, late-onset hepatic failure,“acute-on-chronic”liver failure, augmentation of chemotherapeuticeffect, preventing or treating activity of cytomegalovirus infection,HCMV infection, and antiinflammatory activity.

For certain of the abovementioned conditions it is clear that thecompounds may be used prophylactically as well as for the alleviation ofacute symptoms.

References herein to “treatment” or the like are to be understood toinclude such prophylactic treatment, as well as therapeutic treatments.

It is envisaged that the compounds may be particularly useful in thetreatment of multiple sclerosis. This chronic neurological disorderaffects the nerves of the central nervous system. As discussed earliermost nerves in the body are normally insulated by a protective sheath offatty substance called myelin. Multiple sclerosis causes demyelination,in which this protective sheath becomes inflamed and ultimatelydestroyed.

By modulating or changing the immune system response that is thought tobe responsible for the attack on the central nervous system it should bepossible to attack the cause of the disease itself, rather than the moretraditional method of controlling the symptoms.

The nature of the disease is such that it may be possible to controlmultiple sclerosis without unduly suppressing the patient's immunesystem. Based on the earlier discussed chronically activated humanT-lymphocytes study, it is speculated that multiple sclerosis may be aproduct of chronically activated T-cells having a channel phenotypecharacterised by high expression of Kv1.3 channels and low numbers ofIKCa1 channels. As this channel phenotype is distinct from that seen inquiescent and acutely activated cells it may provide a useful means forcontrolling multiple sclerosis without the significant side effects ofless specific drugs.

Furthermore, in demyelinating diseases such as multiple sclerosis ordiabetic neuropathy, the destruction of the myelin sheath evokes aninternodal potassium current in myelinated nerve fibers by uncoveringnormally silent potassium channels. These abnormal potassium currentscontribute to the conduction failure observed in demyelinated neurons.Blockers of axonal potassium channels such as the unselective compound4-aminopyridine (4-AP) have been demonstrated to overcome conductionfailure in vitro and to improve disability in certain multiple sclerosispatients. 4-AP (Fampridine) is currently in clinical trials for multiplesclerosis. Compounds that block both the Kv1.3 channel in autoreactiveT-cells and the Kv1.1-Kv1.2 heteromultimeric channels present in theRanvier Nodes of myelinated nerves might be ideally suited for thetreatment of multiple sclerosis. Such compounds could simultaneouslyenhance impulse propagation in demyelinated neurons and modify theimmune response.

Thus in another aspect of the invention there is provided a method ofpreventing or treating autoimmune or chronic inflammatory diseases, theprevention of rejection of foreign organ transplants and/or relatedafflictions, said method including the step of administrating a compoundof formula I or Ia, or salt thereof, or a composition comprising thecompound or salt thereof.

Accordingly in a preferred form of the invention, there is provided ameans for controlling multiple sclerosis by the application of a blockerof the Kv1.3 channel, preferably a selective channel blocker of theKv1.3 channel, and optionally also a blocker of Kv1.1 and/or Kv1.2channels, by the application of a compound of formulae I/Ia or saltthereof, including a pharmaceutically acceptable derivative thereof, ora composition comprising the compound of formula I or salt thereof, or apharmaceutically acceptable derivative thereof.

In another preferred form of the invention there is provided a methodfor preventing or treating diabetes including the step of administratinga compound of formulae I/Ia or a pharmaceutically acceptable saltthereof, including a pharmaceutically acceptable derivative thereof, ora composition comprising the compound or pharmaceutically acceptablesalt thereof, or pharmaceutically acceptable derivative thereof.

In a further aspect, the invention provides a method of modulatingpotassium ion channel activity of T-cells by the application of acompound of Formulae I/Ia or a pharmaceutically acceptable salt thereof,including a pharmaceutically acceptable derivative thereof, or acomposition comprising the same, to said T cells. Preferably thecompounds of the invention inhibit the potassium ion channel activity ofT-cells.

Preferably the potassium channel activity inhibited by the compound ofFormulae I/Ia is a voltage-gated potassium channel, for example,Kv1.1-Kv1.7. More preferably the potassium ion channel activity is thevoltage-gated potassium channel, Kv1.3 of a T-cell. Preferably thecompound selectively inhibits the Kv1.3 channel, and optionally also theKv1.1 and/or Kv1.2 channels.

In a further aspect of the present invention, there is provided the useof a compound of formulae I/Ia or salt thereof, in the preparation of amedicament for the treatment (therapeutic or prophylactic) of diseasestates mediated by potassium channels, and in particular by blocking theKv1.3 channel.

In a further aspect of the invention there is provided a process for theproduction of the compounds of Formulae I/Ia or salts thereof, includingpharmaceutically acceptable derivatives thereof.

The compounds of the invention can be made from khellin, a naturalproduct from plants which is cheap and commercially available. A generalsynthetic scheme is set out below for those compounds where R₅ ismethyl, and R₃ and R₄ includes an oxygen atom linking it to the parentstructure:—

Where L is a halide leaving group and R_(a) and R_(b) are independentlyselected from optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted C₃₋₇ cycloalkyl, optionally substitutedC₄₋₇ cycloalkenyl, optionally substituted alkynyl, i.e., where R₃ and R₄are optionally substituted alkoxy, optionally substituted alkenyloxy,optionally substituted alkynyloxy, C₃₋₇ cycloalkyloxy, and C₄₋₇cycloalkenyloxy.

The vinylogous ester containing six-membered ring of khellin acts as aprotecting group for the ultimate phenol and acetyl functionalitiesduring the manipulations of the ethers. An alternate synthesis fromkhellinone can be envisaged where the phenol at the 6-position is cappedwith a suitable protecting group.

Compounds of the invention where R_(b) is other than Me may besynthesised in accordance with the following scheme. This scheme ispreferred when the reaction with the alkyl halide is facile.

The alternative reaction scheme is preferred when the reaction with analkyl halide is slow, due to, for instance, the low reactivity of alkylhalides such as alkyl chlorides. The scheme begins with the preparationof 7-desmethylkhellin, which can then be used to prepare the compoundsof the invention.

Synthesis of intermediate 7-desmethylkhellin

Synthesis of compounds of formula I or Ia when R_(b) is other than Me.

A preferred embodiment of the compounds of the present invention arecompounds where R₄ is an aryl-(CH₂)_(n)—O— substituted example (i.e.,where R_(b) is Ar—(CH₂)_(n)—, where n is 1 to 6). An alternativesynthesis for this subset of compounds is shown below. Sonogashiracoupling of 7-alkynyl khellin with an aryl iodide may furnish an arylalkyne, which upon hydrogenation, reoxidation of the benzofuran, andhydrolysis may afford the desired aryl-(CH₂)_(n)—O— khellin. Heckcoupling of 7-allyl khellin offers an alternate pathway to this class ofcompounds. Suitable coupling agents are known in the art and includePd(PPh₃)₂Cl₂, Pd(PPh₃)₄, Pd(dibenzylideneacetone), and PdCl₂(CH₃CN)₂.Preferably the palladium catalysed coupling reactions include aco-catalyst, for instance, CuI, in the presence of a suitable base suchas a trialkylamine base.

4-alkyl or 7-alkyl khellinones may be synthesised by the followingprophetic schemes.

Starting with 7-triflyl khellin (or the 7-bromo visnagin (not shown))Sonogashira coupling with an alkyne may provide the disubstitutedalkyne. Reduction of the alkyne, followed by selective oxidation andalkaline hydrolysis, may give the 7-alkyl khellinone. Note that ananalogous preparation could be envisaged for the generation of 4-alkylkhellinones starting from 4-triflyl khellin.

The L-R₆ group of the compounds of the present invention may beintroduced according to the above scheme, where Hal represents ahalogen.

As an alternative to the above Hal-L-R₆ could be a group Hal-L-Hal, asshown below:

In the above scheme HR₆ is preferably a phenol, thiol or selenol.

Substituted benzofurans can be prepared by electrophilic aromaticsubstitution of the furan ring, including halogenation followed bypalladium mediated coupling. Alternatively, the ring can be deprotonatedusing a base and an electrophile added or a palladium mediated couplingperformed. Other approaches include ring opening the furan to give anortho-formylphenols or salicilates that can be ring closed againintroducing substituents.

The above scheme illustrates that the reduced compounds (i.e., thosewhere

is a single bond) can be prepared by standard hydrogenation techniques,for instance, in the presence of 5% palladium on charcoal.

Compounds of formulae I/Ia where R₅ is other than Me may be prepared bytransformation of the C-5 acetyl group in the kellinones referred toabove. For instance the reaction of this group with an α-haloester inthe presence of zinc (i.e. under Reformatsky conditions) may afford aβhydroxyester which may then be suitably oxidized to form a3-carbonylester (i.e. where —C(O)—R₅ is —C(O)—CR′R″-CO₂R (where R′ andR″ are independently selected from H and lower alkyl, and R is loweralkyl, optionally substituted alkyl, optionally substituted aryl oroptionally substituted arylalkyl).

Also, further substituents for R₅ can be added by initially halogenatingthe C-5 acetyl group with, for instance, Br₂ to form —C(O)CH₂Br.Substitution of the halogen with a suitable nucleophilic group mayafford —C(O)R₅ where R₅ is —CH₂OR, and —CH₂SR, (where R is selected fromhydrogen, optionally substituted alkyl, optionally substituted alkenyl,optionally substituted alkynyl, optionally substituted C₃₋₇ cycloalkyl,optionally substituted heterocyclyl, optionally substituted heteroaryl,and optionally substituted aryl), or CH₂NR′R″ (where R′ and R″ areindependently selected from hydrogen or lower alkyl).

Furthermore, with the use of excess base and a halogen, the acetylmethyl group can be trihalogenated and cleaved via the haloform reactionto form a carboxylic acid (i.e. where R₅ is OH). Further transformationof the carboxylic acid, under conditions known in the art may produceesters (where R₅ is OR) and amides (where R₅ is —NR′R″).

Also, the methyl or methylene groups a to the carbonyl (e.g. where R₅ isCH₃ or CH₂CH₃) can be oxidized with selenium dioxide to giverespectively, α ketoaldehydes (i.e. R₅ is —C(O)H) and α-diketones (i.e.R₅ is —C(O)CH₃). In addition reacting the C-5 acetyl with an appropriatebase and reacting the formed enolate with suitable acyl halides ordialkylcarbonates may afford compounds where R₅ is —CH₂C(O)R and—CH₂C(O)OR respectively, where R is preferably lower alkyl.

In the above schemes the following abbreviations were used:—

TFA trifluoroacetic acid

PMBCI para methoxybenzyl chloride

DMAP dimethylaminopyridine

Aq aqueous

Tf₂O triflic anhydride

Another variation is to add, remove or modify the substituents of theproduct to form new derivatives. This could be achieved by usingstandard techniques for functional group inter-conversion, well known inthe industry such as those described in Comprehensive organictransformations: a guide to functional group preparations by Larock R C,New York, VCH Publishers, Inc. 1989.

Examples of possible functional group inter-conversions are: —C(O)NRR′from —CO₂CH₃ by heating with or without catalytic metal cyanide, e.g.NaCN, and HNRR′ in CH₃OH; —OC(O)R from —OH with e.g., ClC(O)R′ inpyridine; —NR—C(S)NR′R″ from —NHR with an alkylisothiocyanate orthiocyanic acid; —NRC(O)OR from —NHR with alkyl chloroformate;—NRC(O)NR′R″ from —NHR by treatment with an isocyanate, e.g. HN═C═O orRN═C═O; —NRC(O)R′ from —NHR by treatment with ClC(O)R′ in pyridine;—C(═NR)NR′R″ from —C(NR′R″)SR′″ with H₃NR⁺OAc⁻ by heating in alcohol;—C(NR′R″)SR from —C(S)NR′R″ with R—I in an inert solvent, e.g. acetone;—C(S)NR′R″ (where R′ or R″ is not hydrogen) from —C(S)NH₂ with HNR′R″;—C(═NCN)—NR′R″ from —C(═NR′R″)—SR with NH₂CN by heating in anhydrousalcohol, alternatively from —C(═NH)—NR′R″ by treatment with BrCN andNaOEt in EtOH; —NR—C(═NCN)SR from —NHR′ by treatment with (RS)₂C═NCN;—NR″SO₂R from —NHR′ by treatment with ClSO₂R by heating in pyridine;—NR′C(S)R from —NR′C(O)R by treatment with Lawesson's reagent[2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide];—NRSO₂CF₃ from —NHR with triflic anhydride and base, —CH(NH₂)CHO from—CH(NH₂)C(O)OR′ with Na(Hg) and HCl/EtOH; —CH₂C(O)OH from —C(O)OH bytreatment with SOCl₂ then CH₂N₂ then H₂O/Ag₂O; —C(O)OH from —CH₂C(O)OCH₃by treatment with PhMgX/HX then acetic anhydride then CrO₃; R—OC(O)R′from RC(O)R′ by R″CO₃H; —CCH₂OH from —C(O)OR′ with Na/R′OH; —CHCH₂ fromCH₂CH₂OH by the Chugaev reaction; —NH₂ from —C(O)OH by the Curtiusreaction; —NH₂ from —C(O)NHOH with TsCl/base then H₂O; —CHC(O)CHR from—CHCHOHCHR by using the Dess-Martin Periodinane regent orCrO₃/aqH₂SO₄/acetone; —C₆H₅CHO from —C₆H₅CH₃ with CrO₂Cl₂; —CHO from —CNwith SnCl₂/HCl; —CN from —C(O)NHR with PCl₅; —CH₂R from —C(O)R withN₂H₄/KOH; —S(O)₂R from —SR with mCPBA.

In order that the present invention may be more readily understood, weprovide the following non-limiting examples.

EXAMPLES General Procedure

Synthetic Experimental

General Procedures

General Procedure A: Alkylation of Phenols and thiophenols:

A suspension of the phenol (1.0 equiv., 0.2 M), Cs₂CO₃ or K₂CO₃ (1.5equiv.) and alkyl or benzyl halide (generally 1.2 equiv.) in anhydrousdimethylformamide was stirred under N₂ at 60° C. until completion asdetermined by TLC (3-5 h). The reaction mixture was then diluted withethyl acetate and washed twice with either 10% citric acid or 2M HCl andthen brine, dried over MgSO₄, and concentrated in vacuo. The crudeproduct was purified by flash chromatography.

General Procedure B: Hydrolysis of Chromenones

To a solution of the chromenone (0.1-0.2 M) in ethanol (2 parts) atreflux was added slowly 3M NaOH (1 part) and the resulting solution wasstirred at 90° C. for 3 h. The reaction mixture was acidified with 2MHCl and then extracted twice with ethyl acetate. The pooled organicswere washed with brine, dried over MgSO₄ and concentrated in vacuo. Ifnecessary the crude product was purified by silica-gel flashchromatography.

General Procedure C: Alkylations of Aniline

To a solution of the alkyl bromide (1 eq, 0.3-0.4 M) inN-methylpyrrolidinone was added aniline (3 eqs) and the reaction stirredat 90-95° C. for 16 h. The reaction was cooled, quenched with 10% citricacid and extracted with ethyl acetate or dichloromethane. The organiclayer was washed with water and brine, dried over MgSO₄ and concentratedin vacuo. The crude residue was purified by silica-gel flashchromatography.

General Procedure D: Demethylation of 9-Methoxy Analogues

A solution of the methyl ether (1.0 eq.) in dichloromethane (0.2 M) wascooled to −78° C. and a solution of BBr₃ in dichloromethane (1M, 1.5eq.) was added over 2 min. The reaction mixture was stirred at −78° C.for 10 min then at rt overnight. The reaction vessel was placed into anice-bath and water was added to quench the reaction. The dichloromethanewas removed in vacuo and the resulting suspension was acidified withdilute citric acid to give a final concentration of 2% citric acid. Thesuspension was heated at 70° C. for 1 h then filtered, washing withwater. The resulting solid was dried under high vacuum to give theproduct.

General Procedure E: Alkylations of Amines and N-Heterocycles

To a solution of the bromide (0.2-0.5 M) in anhydrous dimethylformamidewas added the amine or N-heterocycle (3-6 eqs) and the reaction wasstirred at 80-90° C. under a N₂ atmosphere until the reaction wascomplete by TLC (˜5 h). The reaction was quenched with saturated aqueousNH₄Cl solution and extracted with ethyl acetate. The organic layer waswashed with water then brine, dried over MgSO₄ and concentrated undervacuum. The crude residue was purified by silica gel flashchromatography.

General Procedure F: Hydrogenation of Benzofuran Derivatives

A suspension of the benzofuran (1.0 eq.), and 10% palladium on carbon(20% by weight) in methanol (0.1 M) was stirred under H₂ at it for 16 h.The reaction mixture was filtered through a Celite pad, washing withmethanol and dichloromethane. The solvent was concentrated in vacuo andthe crude product was purified by flash chromatography when required.

General Procedure G: 4-Alkylation of Khellin Derivatives

The khellin and khellinone derivatives which were alkylated at the4-position were generally synthesised in accordance with the followinggeneral reaction scheme.

Step 1: Phenol derivative i (1.0 eq., 0.2 M) was dissolved in dry DCMand cooled to 0° C. under N₂. Anhydrous pyridine (4.0 eq.) was added toit, followed by triflic anhydride (1.5 eq.) slowly under N₂. Thereaction temperature was slowly raised to it and stirred overnight underN₂. The reaction was cooled and quenched by addition of aqueous NH₄Cl(saturated) solution and extracted with DCM. The organic layer wasseparated, dried over MgSO₄ (anhydrous), filtered and concentrated undervacuum. The dark brownish residue was subjected to flash columnchromatography to give crude triflate ii as a solid, which was used assuch without further purification.

Step 2: ZnBr₂.2H₂O (4.0 eq.) was dried at 115-120° C. for 2.0 h in RBflask with occasional mixing under high vacuum. After drying, the flaskwas cooled to rt under N₂ and then dissolved in dry tetrahydrofuran (6ml for 800 mg of ZnBr₂). The clear solution was cooled to −78° C. underN₂ atmosphere and then 4.0 mmol of RLi (MeLi was 1.6 M in diethyletherand EtLi was 0.5 M in benzene/cyclohexane 9/1) was added slowly bysyringe. The reaction temperature was allowed to warm to it slowly andstirred for 15 min and then again cooled to −78° C. under N₂ atmosphere.CuI (0.15 eq.) and PdCl₂(PPh₃)₂ (0.12 eq.) were added to the reactionmixture and the reaction vessel was evacuated and back-filled with N₂.The triflate derivative ii (R₁=Me or 3-phenylpropyl) (1.0 eq.),dissolved in the minimum amount of dry tetrahydrofuran, was added andagain flushed with N₂. The reaction mixture was stirred at roomtemperature for 48 hours. After this the reaction was cooled to 0° C.and quenched by addition of aqueous NH₄Cl solution and extracted withethyl acetate. The organic layer was dried over MgSO₄, evaporated andthe crude residue was purified by flash chromatography usingdichloromethane as eluent to afford iii.

Step 3: Khellin derivative iii (0.22 mmol) was dissolved in a mixture of2 ml of ethanol (2 mL) and 3 M NaOH (1 mL). The reaction mixture washeated at 85-95° C. for 3 hours and then cooled to rt. The reaction wasdiluted with 10% citric acid (10 mL) and then extracted with ethylacetate (20 mL) and washed with water. The organic layer was separated,dried over MgSO₄ and evaporated under vacuum. The residue was purifiedby flash chromatography using dichloromethane as eluent to afford iv.

General Procedure H:

A suspension of the phenol (1.0 eq.), Cs₂CO₃ (2.0 eq.), Kl (2.0 eq.) andthe alkyl chloride (1.5 eq.) in anhydrous dimethylformamide (2 ml) wasstirred under N₂ at a temperature between 60° C. and 85° C. for between16 h and 48 h. After this time the reaction was cooled, quenched withwater (20 ml) and extracted with ethyl acetate (20 ml). The organiclayer was washed with water (2×20 ml) and brine (10 ml), dried overMgSO₄ and concentrated in vacuo. The crude residue was purified by flashchromatography.

General Procedure I:

To a stirred suspension the phenol (1.0 eq.), K₂CO₃ (2.0 eq.) and NaI(0.30 eq.), predried under vacuum at 100° C. for 5 h) in drydimethylformamide or dimethylsulfoxide (0.1 M of phenol) was added thealkyl chloride (2.0 eq.) and the reaction was heated at 60° C. for 16 h.After this time the reaction was cooled, diluted with ethyl acetate andwashed thrice with water. The organic layer was dried over MgSO₄,concentrated in vacuo and the crude residue was purified by silica-gelflash chromatography

Example 1

5-Acetyl-4,7-dimethoxy-6-(3-(phenyl)propoxy)benzofuran

Khellinone (59 mg, 0.25 mmol) and 3-(phenyl)propylbromide (46 μL, 0.30mmol) were treated as described under General Procedure A to afford thetitle compound (76 mg, 85%) as a colourless solid: ¹H NMR (300 MHz,CDCl₃): δ 2.03 (m, 2H), 2.53 (s, 3H), 2.76 (t, J=7.8 Hz, 2H), 3.97 (s,3H), 4.03 (s, 3H), 4.08 (t, J=6.3 Hz, 2H), 6.86 (d, J=2.4 Hz, 1H),7.14-7.30 (m, 5H), 7.56 (d, J=2.4 Hz, 1H). MS (ES⁺) m/z 355.1 (M+H⁺).

Example 2

5-Acetyl-4,7-dimethoxy-6-(4-(phenoxy)butoxy))benzofuran

Khellinone (55 mg, 0.25 mmol) and 4-(phenoxy)butylbromide (69 mg, 0.30mmol) were treated as described under General Procedure A to afford thetitle compound (73 mg, 78%) as a brown oil: ¹H NMR (300 MHz, CDCl₃): δ1.90 (m, 4H), 2.51 (s, 3H), 3.97 (s, 3H), 3.98-4.04 (m, 5H), 4.11 (t,J=5.9 Hz, 2H), 6.85 (d, J=2.3 Hz, 1H), 6.92 (m, 3H), 7.26 (t, J=8.5 Hz,2H), 7.56 (d, J=2.3 Hz, 1H). MS (ES⁺) m/z 385.0 (M+H⁺).

Example 3

5-Acetyl-6-(3-phenylpropoxy)benzofuran

5-Acetyl-6-hydroxybenzofuran (60 mg, 0.34 mmol) and1-bromo-3-phenylpropane were reacted according to General Procedure A.The crude residue was purified by flash chromatography, eluting withdiethyl ether:petroleum ether (1:9) to afford the title compound as awhite solid (81 mg, 81%). ¹H NMR (300 MHz, CDCl₃): δ 2.26-2.16 (m, 2H),2.69 (s, 3H), 2.85 (t, J=7.3 Hz, 2H), 4.07 (t, J=6.3 Hz, 2H), 6.72 (d,J=1.7 Hz, 1H), 6.99 (s, 1H), 7.32-7.19 (m, 5H), 7.54 (d, J=2.2 Hz, 1H),7.99 (s, 1H). MS (ES⁺) m/z 294.9 (M+H⁺).

Example 4

4a) 9-methoxy-4,7-dimethyl-5H-furo[3,2-g]chromen-5-one

9-Methoxy-7-methyl-4-trifluoromethanesulfonyl-5H-furo[3,2-g]chromen-5-one(324 mg, 1.0 mmol), ZnBr₂.H₂O (1.04 g, 4.0 mmol), CuI (28 mg, 0.15mmol), PdCl₂(PPh₃)₂ (84 mg, 0.12 mmol) and MeLi (2.5 ml of 1.6 M indiethylether, 4.0 mmol) were treated as described under GeneralProcedure G (Step 2) to afford the title compound (Yield 70%). ¹H NMR(300 MHz, CDCl₃): δ 2.38 (s, 3H, Me), 2.94 (s, 3H, Me), 4.21 (s, 3H,OMe), 6.05 (s, 1H), 6.91 (d, J=2.4, 1H), 7.65 (d, J=2.4, 1H). MS (ES)m/z: 244.9 (M+H⁺).

4b) 5-Acetyl-6-hydroxy-7-methoxy-4-methylbenzofuran

The title compound was prepared from Example 4a) utilising GeneralProcedure G (Step 3) in 65% yield. ¹H NMR (300 MHz, CDCl₃): δ 2.53 (s,3H, Me), 2.64 (s, 3H, Me), 4.13 (s, 3H, OCH3), 6.74 (d, J=2.4, 1H), 7.52(d, J=2.4, 1H), 9.27 (s, 1H, OH). MS (ES) m/z: 220.9 (M+H⁺).

4c) 5-Acetyl-4-methyl-7-methoxy-6-(3-(phenyl)propoxy)benzofuran

Compound from Example 4b) (40 mg, 0.18 mmol), anhydrous K₂CO₃ (50 mg,0.36 mmol) and 1-bromo-3-(phenyl)-propane (43 mg, 0.22 mmol) weretreated according to General Procedure A. The residue was purified byflash column chromatography to offer the title compound in 80% yield. ¹HNMR (300 MHz, CDCl₃) δ: 1.98-2.08 (m, 2H), 2.31 (s, 3H, CH₃), 2.53 (s,3H, OCH₃), 2.76 (t, J=7.6, 2H), 4.04 (t, J=6.3, 2H), 4.10 (s, 3H, OCH₃),6.739d, J=2.1, 1H), 7.15-7.30 (m, 5H), 7.58 (d, J=2.1, 1H). MS (ES) m/z:338.9 (M+H⁺).

Example 5

5a) 5-Acetyl-6-(2-bromoethoxy)-4,7-dimethoxybenzofuran

Khellinone (850 mg, 3.6 mmol, 0.4 M), K₂CO₃ (3 eqs) and1,2-dibromoethane (3 eqs) were reacted according to General Procedure A.The crude product was purified by flash chromatography, eluting withethyl acetate:petroleum ether (15:85) to afford the title compound as aclear oil (1.02 g, 83%). ¹H NMR (300 MHz, CDCl₃): δ 2.53 (s, 3H), 3.57(t, J=6.3 Hz, 2H), 3.98 (s, 3H), 4.07 (s, 3H), 4.35 (t, J=6.3 Hz, 2H),6.86 (d, J=2.2 Hz, 1H), 7.57 (d, J=2.2 Hz, 1H). MS (ES⁺) m/z 342.8/344.8(M+H⁺).

5b) 5-Acetyl-4,7-dimethoxy-6-(2-(phenoxy)ethoxy)benzofuran

Example 5a) (55 mg, 0.16 mmol, 0.1 M), Cs₂CO₃ (2 eqs) and phenol (1.5eqs) were reacted according to General Procedure A. The crude productwas purified by flash chromatography, eluting with ethylacetate:petroleum ether (1:9) to afford the title compound as a clearoil (48 mg, 84%). ¹H NMR (300 MHz, CDCl₃): δ 2.52 (s, 3H), 3.97 (s, 3H),4.07 (s, 3H), 4.22 (m_(c), 2H), 4.42 (m_(c), 2H), 6.86 (d, J=2.1 Hz,1H), 6.91-6.96 (m, 3H), 7.24-7.30 (m, 2H), 7.57 (d, J=2.1 Hz, 1H). MS(ES⁺) m/z 356.9 (M+H⁺).

Example 6

6a) 5-Acetyl-6-(3-bromopropoxy)-4,7-dimethoxybenzofuran

Khellinone (400 mg, 1.7 mmol, 0.3 M), K₂CO₃ (3 eqs) and1,3-dibromopropane (3 eqs) were reacted according to General ProcedureA. The crude product was purified by flash chromatography, eluting withethyl acetate:petroleum ether (15:85) to afford the title compound as aclear oil (530 mg, 88%). ¹H NMR (300 MHz, CDCl₃): δ 2.24 (quintet, J=6.2Hz, 2H), 2.51 (s, 3H), 3.57 (t, J=6.6 Hz, 2H), 3.97 (s, 3H), 4.07 (s,3H), 4.19 (t, J=6.4 Hz, 2H), 6.86 (d, J=2.2 Hz, 1H), 7.56 (d, J=2.2 Hz,1H). MS (ES⁺) m/z 356.8/358.8 (M+H⁺).

6b) 5-Acetyl-4,7-dimethoxy-6-(3-(phenoxy)propoxy)benzofuran

Example 6a) (50 mg, 0.14 mmol, 0.1 M), Cs₂CO₃ (2.5 eqs) and phenol (1.5eqs) were reacted according to General Procedure A. The crude productwas purified by flash chromatography, eluting with ethylacetate:petroleum ether (1:9) to afford the title compound as a clearoil (40 mg, 77%). ¹H NMR (300 MHz, CDCl₃): δ 2.18 (quintet, J=6.2 Hz,2H), 2.48 (s, 3H), 3.96 (s, 3H), 4.00 (s, 3H), 4.13 (t, J=6.2 Hz, 2H),4.24 (t, J=6.1 Hz, 2H), 6.85 (d, J=2.2 Hz, 1H), 6.90-6.94 (m, 3H),7.24-7.29 (m, 2H), 7.55 (d, J=2.2 Hz, 1H). MS (ES⁺) m/z 370.9 (M+H⁺).

Example 7

5-Acetyl-4,7-dimethoxy-6-(2-(thiophenoxy)ethoxy)benzofuran

Example 5a) (55 mg, 0.16 mmol, 0.1 M), K₂CO₃ (2.5 eqs) and thiophenol(1.5 eqs) were reacted according to General Procedure A. The crudeproduct was purified by flash chromatography, eluting with ethylacetate:petroleum ether (1:9) to afford the title compound as a clearoil (55 mg, 92%). ¹H NMR (300 MHz, CDCl₃): δ 2.51 (s, 3H), 3.23 (t,J=7.2 Hz, 2H), 3.96 (s, 3H), 4.01 (s, 3H), 4.21 (t, J=7.1 Hz, 2H), 6.85(d, J=2.2 Hz, 1H), 7.14-7.20 (m, 1H), 7.24-7.29 (m, 2H), 7.36-7.39 (m,2H), 7.55 (d, J=2.2 Hz, 1H). MS (ES⁺) m/z 372.9 (M+H⁺).

Example 8

5-Acetyl-4,7-dimethoxy-6-(3-(phenylthio)propoxy)benzofuran

Example 6a) (50 mg, 0.14 mmol, 0.1 M), K₂CO₃ (2.5 eqs) and thiophenol(1.5 eqs) were reacted according to General Procedure A. The crudeproduct was purified by flash chromatography, eluting with ethylacetate:petroleum ether (1:9) to afford the title compound as a clearoil (50 mg, 92%). ¹H NMR (300 MHz, CDCl₃): δ 1.98-2.07 (m, 2H), 2.50 (s,3H), 3.08 (t, J=7.1 Hz, 2H), 3.97 (s, 3H), 4.04 (s, 3H), 4.15 (t, J=6.0Hz, 2H), 6.85 (d, J=2.2 Hz, 1H), 7.13-7.20 (m, 1H), 7.24-7.29 (m, 2H),7.33-7.36 (m, 2H), 7.56 (d, J=2.2 Hz, 1H). MS (ES⁺) m/z 386.9 (M+H⁺).

Example 9

5-Acetyl-4,7-dimethoxy-6-(2-(benzenesulfonyl)ethoxy)benzofuran

To a solution of the sulfide of Example 7 (25 mg, 0.067 mmol) indichloromethane (1.5 mL) was added meta-chloroperbenzoic acid (50 mg,˜70% purity, 3 eqs) and the reaction was stirred for 16 h at roomtemperature. During this time formation of a precipitate was observed.The reaction was diluted with dichloromethane (20 mL) and quenched withsaturated aqueous NaHCO₃ (20 mL). The organic layer was washed withanother portion of saturated aqueous NaHCO₃ and brine, dried over MgSO₄and concentrated in vacuo. The crude residue was purified by flashchromatography, eluting with ethyl acetate:petroleum ether (3:7) toafford the title compound as a clear resin (14 mg, 52%). ¹H NMR (300MHz, CDCl₃): δ 2.38 (s, 3H), 3.56 (t, J=6.7 Hz, 2H), 3.94 (s, 3H), 4.03(s, 3H), 4.40 (t, J=6.7 Hz, 2H), 6.84 (d, J=2.2 Hz, 1H), 7.52-7.65 (m,4H), 7.94 (d, J=7.2 Hz, 2H). MS (ES⁺) m/z 404.9 (M+H⁺).

Example 10

5-Acetyl-4,7-dimethoxy-6-(3-(benzenesulfonyl)propoxy)benzofuran

To a solution of the sulfide of Example 8 (30 mg, 0.078 mmol) indichloromethane (1.5 mL) was added meta-chloroperbenzoic acid (58 mg,˜70% purity, 3 eqs) and the reaction was stirred for 2.5 h at roomtemperature. The reaction was diluted with dichloromethane (20 mL) andquenched with saturated aqueous NaHCO₃ (20 mL). The organic layer waswashed with another portion of saturated aqueous NaHCO₃ and brine, driedover MgSO₄ and concentrated in vacuo. The crude residue was purified byflash chromatography, eluting sequentially with ethyl acetate:petroleumether (1:3 then 1:2) to afford the title compound as a clear resin (20mg, 61%). ¹H NMR (300 MHz, CDCl₃): δ 2.05-2.14 (m, 2H), 2.45 (s, 3H),3.32 (m_(c), 2H), 3.95 (s, 3H), 4.01 (s, 3H), 4.07 (t, J=5.8 Hz, 2H),6.84 (d, J=2.2 Hz, 1H), 7.54-7.67 (m, 4H), 7.94 (d, J=7.1 Hz, 2H). MS(ES⁺) m/z 418.9 (M+H⁺).

Example 11

5-Acetyl-4,7-dimethoxy-6-(2-(phenylamino)ethoxy)benzofuran

Bromide of Example 5a) (60 mg, 0.17 mmol) was treated according toGeneral Procedure C. The crude product was purified by flashchromatography eluting with ethyl acetate:petroleum ether (1:9) toafford the title compound as a viscous oil (18 mg, 30%). ¹H NMR (300MHz, CDCl₃): δ 2.51 (s, 3H), 3.40 (br t, J=4.8 Hz, 2H), 3.98 (s, 3H),4.05 (s, 3H), 4.29 (t, J=4.8 Hz, 2H), 4.50 (br s, 1H), 6.65-6.71 (m,3H), 6.86 (dd, J=0.7, 2.2 Hz, 1H), 7.16 (t, J=7.8 Hz, 2H), 7.57 (dd,J=0.7, 2.2 Hz, 1H). MS (ES⁺) m/z 355.9 (M+H⁺).

Example 12

5-Acetyl-4,7-dimethoxy-6-(3-(phenylamino)propoxy)benzofuran

Bromide of Example 6a) (60 mg, 0.17 mmol) was treated according toGeneral Procedure C. The crude product was purified by flashchromatography eluting with ethyl acetate:petroleum ether (15:85) toafford the title compound as a viscous oil (48 mg, 77%). ¹H NMR (300MHz, CDCl₃): δ 2.00 (quintet, J=6.1 Hz, 2H), 2.52 (s, 3H), 3.34 (br t,J=6.4 Hz, 2H), 3.98 (s, 3H), 4.05 (s, 3H), 4.14 (t, J=5.8 Hz, 2H),6.63-6.69 (m, 3H), 6.86 (d, J=2.1 Hz, 1H), 7.16 (t, J=8.2 Hz, 2H), 7.57(d, J=2.1 Hz, 1H). MS (ES⁺) m/z 369.9 (M+H⁺).

Example 13

13a) 5-Acetyl-7-N,N-dimethylaminomethyl-6-hydroxy-4-methoxybenzofuran

To a solution of visnaginone (103 mg, 0.50 mmol) in anhydrous ethanol (2mL) was added dimethylamine (116 μL, 0.65 mmol) and formalin (37 wt. %,49 μL, 0.65 mmol) and this was stirred at 90° C. for 16 h beforeconcentrating in vacuo. The resulting residue was purified by flashchromatography eluting with dichloromethane/ethyl acetate (7:3) thenwith dichloromethane/ethyl acetate (7:3) plus 1% triethylamine to affordthe title compound (51 mg, 39%) as a yellow solid: ¹H NMR (300 MHz,CD₃CN): δ 2.30 (s, 6H), 2.53 (s, 3H), 3.79 (s, 2H), 4.07 (s, 3H), 7.00(d, J=2.4 Hz, 1H), 7.58 (d, J=2.4 Hz, 1H). MS (ES⁺) m/z 264.0 (M+H⁺).

13b)5-Acetyl-7-N,N-dimethylaminomethyl-4-methoxy-6-(3-(phenyl)propoxy)benzofuran

Example 13a) (33 mg, 0.13 mmol) and 3-(phenyl)propylbromide (23 μL, 0.15mmol) were treated as described under General Procedure A. The crudeproduct was purified by flash chromatography eluting withdichloromethane/ethyl acetate (7:3) to afford the title compound (18 mg,38%) as a brown solid: ¹H NMR (300 MHz, CDCl₃): δ 2.05 (m, 2H), 2.26 (s,6H), 2.53 (s, 3H), 2.77 (t, J=7.8 Hz, 2H), 3.63 (s, 2H), 3.94 (t, J=6.3Hz, 2H), 4.05 (s, 3H), 6.88 (d, J=2.4 Hz, 1H), 7.15-7.31 (m, 5H), 7.58(d, J=2.4 Hz, 1H). MS (ES⁺) m/z 382.1 (M+H⁺).

Example 14

14a)4-Methoxy-7-methyl-9-(2-(N-morpholino)ethoxy)furo[3,2-g]chromen-5-one

A suspension of 9-desmethylkhellin (123 mg, 0.50 mmol),4-(2-chloroethyl)morpholine hydrochloride (140 mg, 0.75 mmol), caesiumcarbonate (487 mg, 1.5 mmol) and potassium iodide (83 mg, 0.50 mmol) inDMF (2.5 mL) was stirred at 60° C. for 72 h. The reaction mixture wastreated with water (8 mL), then filtered washing with water, and driedto give the title compound (83 mg, 46%) as a brown solid: ¹H NMR (300MHz, CDCl₃): δ 2.35 (s, 3H), 2.69 (m, 4H), 2.91 (m, 2H), 3.76 (m, 4H),4.05 (s, 3H), 4.49 (m, 2H), 6.04 (s, 1H), 7.00 (d, J=2.3 Hz, 1H), 7.60(d, J=2.3 Hz, 1H).

14b) 5-Acetyl-4-methoxy-6-hydroxy-7-(2-(N-morpholino)ethoxy-benzofuran

To a solution of Example 14a) (54 mg, 0.15 mmol) in ethanol (1.5 mL) at60° C. was added 3M NaOH (1.5 mL) and the reaction mixture was stirredat 60° C. for 5 h. The solution was concentrated in vacuo to half itsoriginal volume and the pH was adjusted to pH8 by Universal Indicatorusing 10% citric acid solution and saturated sodium bicarbonatesolution. The solution was extracted with ethyl acetate (3×10 mL) andthe pooled organics were dried over Na₂SO₄ and concentrated in vacuo togive the title compound (25 mg, 46%) as a brown oil: ¹H NMR (300 MHz,CDCl₃): δ 2.64 (s, 3H), 2.75 (m, 4H), 2.83 (t, J=5.2 Hz, 2H), 3.81 (m,4H), 4.07 (s, 3H), 4.32 (t, J=5.2 Hz, 2H), 6.85 (d, J=2.3 Hz, 1H), 7.46(d, J=2.3 Hz, 1H).

14c) 5-Acetyl-4-methoxy-7-(2-(N-morpholino)ethoxy-6-(4-(phenoxy)butoxy))benzofuran

Example 14b) (15 mg, 0.045 mmol) and 4-(phenoxy)butylbromide (12 mg,0.054 mmol) were treated as described under General Procedure A. Thecrude was purified by flash chromatography eluting with dichloromethaneto afford the title compound (13 mg, 59%) as an oil: ¹H NMR (300 MHz,CDCl₃): δ 1.89 (m, 4H), 2.51 (s, 3H), 2.64-2.91 (m, 6H), 3.80 (m, 4H),3.98-4.02 (m, 5H), 4.11 (t, J=5.9 Hz, 2H), 4.42 (m, 2H), 6.86-6.94 (m,4H) 7.26 (m, 2H), 7.55 (d, J=2.2 Hz, 1H).

Example 15

15a) 5-Acetyl-6-hydroxy-4-methoxy-7-(3-(phenyl)propoxy)benzofuran

BNC32 was prepared as described in PCT/AU2006/000333: ¹H NMR (300 MHz,CDCl₃): δ 2.14 (m, 2H), 2.36 (s, 3H), 2.91 (t, 2H), 4.09 (s, 3H), 4.35(t, 2H), 6.11 (s, 1H), 6.99 (d, 1H), 7.00-7.31 (m, 5H), 7.60 (d, 1H). MS(ES⁺) m/z 365.3 (M+H⁺).

15b)5-Acetyl-6-(2-dimethylaminoethoxy)-4-methoxy-7-(3-phenylpropoxy)benzofuran

The title compound was prepared by reacting example 15a) (170 mg, 0.50mmol), Cs₂CO₃ (325 mg, 1.0 mmol), Kl (166 mg, 1.0 mmol) and2-chloroethyldimethylamine hydrochloride (108 mg, 0.75 mmol) asdescribed under General Procedure H. The crude residue was purified byflash chromatography, eluting with ethyl acetate:dichloromethane (1:1then 1:1+5% methanol) to afford the title compound as a brown oil (40mg, 20%). ¹H NMR (300 MHz, CDCl₃): δ 2.06-2.15 (m, 2H), 2.30 (s, 6H),2.53 (s, 3H), 2.65 (t, J=5.9 Hz, 2H), 2.85 (t, J=7.7 Hz, 2H), 3.97 (s,3H), 4.15 (t, J=5.9 Hz, 2H), 4.28 (t, J=6.4 Hz, 2H), 6.85 (d, J=2.2 Hz,1H), 7.15-7.30 (m, 5H), 7.54 (d, J=2.2 Hz, 1H). MS (ES⁺) m/z 412.0(M+H⁺).

Example 16

5-Acetyl-6-(2-morpholinoethoxy)-4-methoxy-7-(3-phenylpropoxy)benzofuran

The title compound was prepared by reacting example 15a) (100 mg, 0.29mmol), Cs₂CO₃ (190 mg, 0.58 mmol), KI (96 mg, 0.58 mmol) and2-chloroethylmorpholine hydrochloride (81 mg, 0.43 mmol) as describedunder General Procedure H. The crude residue was purified by flashchromatography, eluting with ethyl acetate:dichloromethane (1:1+2%methanol) to afford the title compound as a colourless oil (102 mg,78%). ¹H NMR (300 MHz, CDCl₃): δ 2.04-2.14 (m, 2H), 2.50 (m_(c), 4H),2.54 (s, 3H), 2.68 (t, J=5.7 Hz, 2H), 2.85 (t, J=7.7 Hz, 2H), 3.69(m_(c), 4H), 3.97 (s, 3H), 4.17 (5.7 Hz, 2H), 4.27 (t, J=6.4 Hz, 2H),6.85 (d, J=2.2 Hz, 1H), 7.15-7.30 (m, 5H), 7.54 (d, J=2.2 Hz, 1H). MS(ES⁺) m/z 453.9 (M+H⁺).

Example 17

5-Acetyl-6-(2-imidazol-1-ylethoxy)-4-methoxy-7-(3-phenylpropoxy)benzofuran

Example 15a) (500 mg, 1.47 mmol, 0.6 M), K₂CO₃ (2 eqs) and1,2-dibromoethane (3 eqs) were reacted according to General Procedure A.The crude residue was subjected to flash chromatography, eluting withethyl acetate:petroleum ether (1:9) to afford the bromoalkylatedmaterial contaminated with ˜10% of the 6-vinyl derivative (534 mg). Aportion of this crude material (100 mg) was dissolved in anhydrousdimethylformamide (2 ml) and treated with Cs₂CO₃ (150 mg, 0.46 mmol) andimidazole (36 mg, 0.53 mmol). The resulting suspension was stirred underN₂ at 100° C. for 3 h, cooled, quenched with water (20 ml) and extractedwith ethyl acetate (20 ml). The organic layer was washed with water (20ml) and brine (10 ml), dried over MgSO₄ and concentrated in vacuo. Thecrude residue was purified by flash chromatography, eluting with ethylacetate:dichloromethane (1:1+2% methanol) to afford the title compoundas a clear oil (72 mg, 60% over two steps). ¹H NMR (300 MHz, CDCl₃): δ1.94-2.04 (m, 2H), 2.43 (s, 3H), 2.76 (t, J=7.7 Hz, 2H), 3.97 (s, 3H),4.12 (t, J=6.4 Hz, 2H), 4.20-4.23 (m, 2H), 4.28-4.31 (m, 2H), 6.85 (d,J=2.2 Hz, 1H), 6.99 (br s, 1H), 7.05 (br s, 1H), 7.15-7.20 (m, 3H),7.24-7.30 (m, 2H), 7.54 (br s, 1H), 7.55 (d, J=2.2 Hz, 1H). MS (ES⁺) m/z434.9 (M+H⁺).

Example 18

18a) 4,7-dimethyl-9-(3-(phenyl)propoxy)-5H-furo[3,2-g]chromen-5-one

The title compound was prepared by reacting9-methoxy-7-(3-(phenyl)propoxy)-4-trifluoromethane-sulfonyl-5H-furo[3,2-g]chromen-5-one(428 mg, 1.0 mmol), ZnBr₂.H₂O (1.04 g, 4.0 mmol), CuI (28 mg, 0.15mmol), PdCl₂(PPh₃)₂ (84 mg, 0.12 mmol) and MeLi (2.5 ml of 1.6 M indiethylether, 4.0 mmol) as described under General Procedure G (Step 2)in 65% yield. ¹H NMR (300 MHz, CDCl₃): δ 2.08-2.18 (m, 2H), 2.36 (s, 3H,Me), 2.92 (t, J=7.6, 2H, CH₂), 2.96 (s, 3H), 4.39 (t, J=6.3, CH₂), 6.05(s, 1H), 6.92 (d, J=2.1, 1H), 7.16-7.34 (m, 5H), 7.64 (d, J=2.1, 1H). MS(ES) m/z: 348.9 (M+H⁺).

18b) 5-Acetyl-6-hydroxy-4-methyl-7-(3-(phenyl)propoxy)benzofuran

The title compound was prepared from Example 18a) as described underGeneral Procedure G (Step 3) in 65% yield. ¹H NMR (300 MHz, CDCl₃): δ2.07-2.16 (m, 2H), 2.53 (s, 3H, CH₃), 2.65 (s, 3H, CH₃), 2.84 (t, J=7.5,2H), 4.40 (t, J=6.3, 2H), 6.73 (d, J=2.1, 1H), 7.16-7.31 (m, 5H), 7.50(d, J=2.1, 1H), 9.20 (s, 1H, OH). MS (ES) m/z: 324.9 (M+H⁺).

18c)5-Acetyl-6-(2-dimethylaminoethoxy)-4-methyl-7-(3-phenylpropoxy)benzofuran

The title compound was prepared by reacting example 18b) (115 mg, 0.355mmol), Cs₂CO₃ (300 mg, 0.92 mmol), Kl (150 mg, 0.90 mmol) and2-chloroethyldimethylamine hydrochloride (80 mg, 0.56 mmol) as describedunder General Procedure H The crude residue was purified by flashchromatography, eluting with ethyl acetate:dichloromethane (1:1+2%methanol then 1:1+5% methanol) to afford the title compound as acolourless oil (60 mg, 43%). ¹H NMR (300 MHz, CDCl₃): δ 2.07-2.17 (m,2H), 2.29 (s, 6H), 2.31 (s, 3H), 2.54 (s, 3H), 2.64 (t, J=5.9 Hz, 2H),2.86 (t, J=7.7 Hz, 2H), 4.11 (t, J=6.0 Hz, 2H), 4.36 (t, J=6.4 Hz), 6.73(d, J=2.2 Hz, 1H), 7.15-7.30 (m, 5H), 7.56 (d, J=2.2 Hz, 1H). MS (ES⁺)m/z 396.0 (M+H⁺).

Example 19

5-Acetyl-6-(2-morpholinoethoxy)-4-methyl-7-(3-phenylpropoxy)benzofuran

The title compound was prepared by reacting example 18b) (160 mg, 0.49mmol), K₂CO₃ (170 mg, 1.23 mmol), 2-chloroethylmorpholine hydrochloride(100 mg, 0.54 mmol) and sodium iodide (10 mg) as described under GeneralProcedure I The crude residue was purified by flash chromatography,eluting with ethyl acetate:dichloromethane (1:2) to afford the titlecompound as a colourless oil (180 mg, 84%). ¹H NMR (300 MHz, CDCl₃): δ2.06-2.16 (m, 2H), 2.31 (s, 3H), 2.48-2.51 (m, 4H), 2.56 (s, 3H), 2.67(t, J=5.6 Hz, 2H), 2.86 (t, J=7.7 Hz, 2H), 3.68-3.71 (m, 4H), 4.12 (t,J=5.7 Hz, 2H), 4.36 (t, J=6.4 Hz, 2H), 6.73 (d, J=2.2 Hz, 1H), 7.16-7.30(m, 5H), 7.57 (d, J=2.2 Hz, 1H). MS (ES⁺) m/z 438.0 (M+H⁺).

Example 20

20a) 5-Acetyl-6-(2-bromoethoxy)-4-methyl-7-(3-phenylpropoxy)benzofuran

Example 18b) (150 mg, 0.46 mmol, 0.1 M), Cs₂CO₃ (2 eqs) and1,2-dibromoethane (3 eqs) were reacted according to General Procedure A.The crude residue was subjected to flash chromatography, eluting withdiethyl ether:petroleum ether (1:9) to afford the title compound as ayellow oil (140 mg, 70%). ¹H-NMR (300 MHz, CDCl₃) δ 2.08-2.17 (m, 2H),2.31 (s, 3H), 2.55 (s, 3H), 2.86 (t, J=7.7 Hz, 2H), 3.55 (t, J=6.2 Hz,2H), 4.32 (t, J=6.2 Hz, 2H), 4.38 (t, J=6.4 Hz, 2H), 6.74 (d, J=2.1 Hz,1H), 7.16-7.31 (m, 5H), 7.58 (d, J=2.1 Hz, 1H). MS (ES⁺) m/z 430.8/432.8(M+H⁺).

20b)5-Acetyl-6-(2-imidazol-1-ylethoxy)-4-methyl-7-(3-phenylpropoxy)benzofuran

A suspension of Example 20a) (570 mg, 1.32 mmol), Cs₂CO₃ (860 mg, 2.64mmol) and imidazole (180 mg, 2.64 mmol) in anhydrous dimethylformamide(8 ml) was stirred under N₂ at 70° C. for 16 h. After this time thereaction was cooled, quenched with water (30 ml) and extracted withethyl acetate (30 ml). The organic layer was washed with water (2×30 ml)and brine (20 ml), dried over MgSO₄ and concentrated in vacuo. The cruderesidue was purified by flash chromatography, eluting with ethylacetate:dichloromethane (1:1 then 1:1+3% methanol) to afford the titlecompound as a colourless oil (375 mg, 68%). ¹H NMR (300 MHz, CDCl₃): δ1.98-2.08 (m, 2H), 2.29 (s, 3H), 2.36 (s, 3H), 2.78 (t, J=7.7 Hz, 2H),4.19-4.28 (m, 6H), 6.73 (d, J=2.1 Hz, 1H), 6.99 (br s, 1H), 7.07 (br s,1H), 7.16-7.20 (m, 3H), 7.24-7.30 (m, 2H), 7.54 (br s, 1H), 7.58 (d,J=2.2 Hz, 1H). MS (ES⁺) m/z 418.9 (M+H⁺).

Example 21

21a)5-Acetyl-6-[2-(5-aminotetrazol-2-yl)ethoxy]-4-methyl-7-(3-phenylpropoxy)benzofuran21b)5-Acetyl-6-[2-(5-aminotetrazol-1-yl)ethoxy]-4-methyl-7-(3-phenylpropoxy)benzofuran

A suspension of the bromide of Example 20a) (70 mg, 0.16 mmol), Cs₂CO₃(106 mg, 0.32 mmol) and 5-aminotetrazole (28 mg, 0.32 mmol) in anhydrousdimethylformamide (1.5 ml) was stirred under N₂ at 90° C. for 16 h.After this time the reaction was cooled, quenched with 1M HCl (20 ml)and extracted with ethyl acetate (20 ml). The organic layer was washedwith water (20 ml) and brine (10 ml), dried over MgSO₄ and concentratedin vacuo. The crude residue was purified by flash chromatography,eluting with ethyl acetate:dichloromethane (1:2) to afford the titlecompound 21 a) as a colourless oil (26 mg, 37%). ¹H NMR (300 MHz,CDCl₃): δ 2.02-2.12 (m, 2H), 2.28 (s, 3H), 2.37 (s, 3H), 2.82 (t, J=7.7Hz, 2H), 4.26 (br s, 2H), 4.31 (t, J=6.4 Hz, 2H), 4.48 (t, J=5.3 Hz,2H), 4.70 (t, J=5.2 Hz, 2H), 6.72 (d, J=2.2 Hz, 1H), 7.16-7.31 (m, 5H),7.57 (d, J=2.2 Hz, 1H). MS (ES⁺) m/z 435.9 (M+H⁺).

Further elution with ethyl acetate:dichloromethane (1:1, 2:1, 1:0)afforded the title compound 21b) as a resin that slowly crystallised (24mg, 34%). ¹H NMR (300 MHz, CDCl₃): δ 1.96-2.05 (m, 2H), 2.30 (s, 3H),2.40 (s, 3H), 2.74 (t, J=7.7 Hz, 2H), 4.31 (t, J=6.6 Hz, 2H), 4.38-4.44(m, 4H), 5.14 (br s, 2H), 6.72 (d, J=2.1 Hz, 1H), 7.14-7.19 (m, 3H),7.24-7.29 (m, 2H), 7.57 (d, J=2.1 Hz, 1H). MS (ES⁺) m/z 435.9 (M+H⁺).

Example 22

22a) 7-Methyl-9-(3-(phenyl)propoxy)-5H-furo[3,2-g]chromen-5-one

9-(3-Phenylpropoxy)-7-methyl-4-trifluoromethanesulfonyl-5H-furo[3,2-g]chromen-5-one(1.5 g, 3.11 mmol, 0.2M, prepared from the corresponding 4-hydroxysystem according to General Procedure G, Step 1) was dissolved inanhydrous dimethylformamide and treated with triethylammonium formate(1.8 g, 12.4 mmol.). The reaction flask was evacuated and back-filledwith N₂ three times. Anhydrous triethylamine (0.63 g, 6.20 mmol),Pd(OAc)₂ (70 mg, 0.31 mmol) and triphenylphosphine (0.16 mg, 0.62 mmol)were added to the reaction mixture and the flask was again evacuated andback-filled with N₂. The reaction mixture was heated to 60-70° C. for 24hours under a N₂ atmosphere. The solvents were removed under vacuum andthe residue was dissolved in ethyl acetate and washed with saturatedaqueous NH₄Cl solution. The organic layer was dried over MgSO₄,concentrated under vacuum and the crude residue was purified by silicagel chromatography, eluting with diethyl ether:dichloromethane (0:1,then 1:3) to afford the title compound as a pale yellow solid (75%). ¹HNMR (300 MHz, CDCl₃) δ: 2.06-2.16 (m, 2H), 2.41 (s, 3H, CH₃), 2.92 (t,J=7.5 Hz, 2H), 4.49 (t, J=6.6 Hz, 2H), 6.15 (s, 1H), 6.85 (d, J=2.1 Hz,1H), 7.16-7.30 (m, 5H), 7.69 (d, J=2.1 Hz, 1H), 8.09 (s, 1H). MS (ES⁺)m/z: 335 (M+H⁺).

22b) 5-Acetyl-6-hydroxy-7-(3-(phenyl)propoxy)benzofuran

Example 22a) (760 mg, 2.27 mmol) was reacted according to GeneralProcedure B to afford the title compound as a pale yellow oil (68 mg,10%). ¹H NMR (300 MHz, CDCl₃) δ: 2.06-2.16 (m, 2H), 2.68 (s, 3H, CH₃),2.88 (t, J=7.5 Hz, 2H), 4.35 (t, J=6.6 Hz, 2H), 6.71 (d, J=2.1 Hz, 1H),7.13-7.29 (m, 5H), 7.55 (d, J=2.1 Hz, 1H), 7.72 (s, 1H), 12.30 (bs, 1H,OH). MS (ES⁺) m/z: 311 (M+H⁺).

22c) 5-Acetyl-6-(2-morpholin-4-yl-ethoxy)-7-(3-phenylpropoxy)benzofuran

The title compound was prepared by reacting example 22b) (60 mg, 0.19mmol) and K₂CO₃ (58 mg, 0.42 mmol), 4-(2-chloroethyl)morpholinehydrochloride (45 mg, 0.24 mmol) as described under General Procedure H.The crude residue was purified by silica-gel flash chromatography,eluting with dichloromethane:ethyl acetate (2:1 then 1:1) to provide thetitle compound as a colourless oil (57 mg, 71%). ¹H-NMR δ 2.08-2.18 (m,2H), 2.48-2.51 (m, 4H), 2.69 (s, 3H), 2.71 (t, J=5.6 Hz, 2H), 2.87 (t,J=7.4 Hz, 2H), 3.66-3.69 (m, 4H), 4.22 (t, J=5.6 Hz, 2H), 4.40 (t, J=6.3Hz, 2H), 6.74 (d, J=2.1 Hz, 1H), 7.16-7.31 (m, 5H), 7.53 (s, 1H), 7.58(d, J=2.1 Hz, 1H). MS (ES⁺) m/z: 424 (M+H).

Example 23

23a) 4-Hydroxy-7-methyl-furo[3,2-g]chromen-5-one

To a suspension of visnagin (920 mg, 4.0 mmol) in dichloromethane (20mL) at −78° C. was added a solution of boron trichloride (1.0 M, 4.0 mL,4.0 mmol) and the reaction mixture was stirred at −78° C. for 15 minthen rt for 16 h. The reaction mixture was cooled to 0° C. and water (25mL) was added slowly at first. The organics were concentrated in vacuoand the resulting suspension was diluted with 5% citric acid (150 mL)and heated at 60° C. for 1 h. The suspension was filtered, washing withwater (3×50 mL) and the resulting solid was dried in a vacuum oven toafford the title compound as a yellow solid (710 mg, 83%): ¹H NMR (300MHz, CDCl₃): δ 2.38 (s, 3H), 6.06 (s, 1H), 6.97 (d, J=2.2 Hz, 1H), 6.99(s, 1H), 7.55 (d, J=2.2 Hz, 1H), 13.52 (s, 1H). MS (ES⁺) m/z 217.2(M+H⁺).

23b) 4-(4-(phenoxy)butoxy)-7-methyl-furo[3,2-g]chromen-5-one

Example 23a) (43 mg, 0.20 mmol) and 4-(phenoxy)butylbromide (55 mg, 0.24mmol) were treated as described under General Procedure A. The crudeproduct was purified by flash chromatography eluting with ethylacetate/petroleum ether (1:4) to afford the title compound (51 mg, 70%)as a colourless solid: ¹H NMR (300 MHz, CDCl₃): δ 2.06 (m, 4H), 2.32 (s,3H), 4.06 (t, J=5.7 Hz, 2H), 4.33 (t, J=5.7 Hz, 2H), 6.04 (s, 1H),6.86-6.96 (m, 4H), 7.22-7.27 (m, 3H), 7.57 (d, J=2.3 Hz, 1H). MS (ES⁺)m/z 365.2 (M+H⁺).

23c) 5-Acetyl-4-(4-(phenoxy)butoxy)-6-hydroxybenzofuran

Example 23b) (36 mg, 0.10 mmol) was treated as described under GeneralProcedure B to afford the title compound (30 mg, 88%) as a brown solid:¹H NMR (300 MHz, CDCl₃): δ 1.96-2.15 (m, 4H), 2.73 (s, 3H), 4.05 (t,J=5.7 Hz, 2H), 4.51 (t, J=6.3 Hz, 2H), 6.69 (s, 1H), 6.84-6.97 (m, 4H),7.24-7.30 (m, 2H), 7.40 (d, J=2.4 Hz, 1H). MS (ES⁺) m/z 341.0 (M+H⁺).

23d) 5-Acetyl-6-(2-morpholin-4-yl-ethoxy)-4-(4-phenoxybutoxy)benzofuran

The title compound was prepared by reacting example 23c) (51 mg, 0.15mmol), K₂CO₃ (41 mg, 0.30 mol) and NaI (8 mg, 0.05 mmol,) and4-(2-chloroethyl)morpholine hydrochloride (33 mg, 0.18 mmol) asdescribed under General Procedure I. The crude residue was purified bysilica-gel flash chromatography, eluting with dichloromethane:ethylacetate (7:3, then 7:3+1% methanol) to afford the title compound as acolourless oil (46 mg, 68%). ¹H-NMR (CDCl₃) δ 1.91-1.96 (m, 4H), 2.50(s, 3H), 2.60-2.75 (br m, 4H), 2.80-2.95 (br m, 2H), 3.70-3.85 (br m,4H), 3.99-4.02 (m, 2H), 4.15-4.30 (br m, 2H), 4.39-4.33 (m, 2H), 6.75(d, J=0.8 Hz, 1H), 6.79 (dd, J=2.3, 0.9 Hz, 1H), 6.86-6.95 (m, 3H),7.22-7.29 (m, 2H), 7.48 (d, J=2.3 Hz, 1H). MS (ES⁺) m/z: 454 (M+H).

Example 24

3-[6-(2-Morpholin-4-ylethoxy)-4-(4-phenoxybutoxy)benzofuran-5-yl]-3-oxo-propionicacid ethyl ester

A suspension of finely cut sodium (21 mg, 0.91 mmol) and Example 23d)(40 mg, 0.09 mmol) in diethyl carbonate (0.65 ml) was heated to 90° C.for 1.5 h then left at 70° C. overnight. After this time the reactionwas cooled, quenched with ethanol (1 ml) and partitioned over water anddichloromethane. The aqueous phase was acidified to pH 4 with 10% citricacid and then to pH8 with saturated NaHCO₃. The aqueous phase wasextracted with dichloromethane (2×) and the combined organic layers weredried over NaS₂O₄ and concentrated in vacuo. The crude residue waspurified by silica-gel flash chromatography, eluting withdichloromethane:ethyl acetate (1:1, then 1:1+1% methanol) to give thetitle compound as an oil (15 mg, 33%). ¹H-NMR (CDCl₃) δ 1.20 (t, J=7.1Hz, 3H), 1.94-1.98 (m, 4H), 2.57 (br m, 4H), 2.80 (br t, 2H), 3.70-3.72(m, 4H), 3.90 (s, 2H), 3.99-4.03 (m, 2H), 4.10-4.15 (m, 2H), 4.14 (q,J=7.1 Hz, 2H), 4.30-4.34 (m, 2H), 6.74 (d, J=0.8 Hz, 1H), 6.79 (dd,J=2.3, 0.9 Hz, 1H), 6.86-6.94 (m, 3H), 7.22-7.28 (m, 2H), 7.47 (d, J=2.3Hz, 1H). MS (ES⁺) m/z: 526 (M+H).

Example 25

5-Acetyl-6-(2-dimethylamino-ethoxy)-4-(4-phenoxybutoxy)benzofuran

The title compound was prepared by reacting example 23c) (34 mg, 0.10mmol), K₂CO₃ (31 mg, 0.22 mol), NaI (5 mg, 0.03 mmol) and2-(dimethylamino)ethylchloride hydrochloride (34 mg, 0.24 mmol) asdescribed under General Procedure I. The crude residue was purified bysilica-gel flash chromatography, eluting with dichloromethane thendichloromethane:methanol (19:5) to afford the title compound as acolourless oil (13 mg, 32%). ¹H-NMR (CDCl₃) δ 1.92-1.96 (m, 4H), 2.45(s, 6H), 2.49 (s, 3H), 2.88-2.91 (m, 2H), 3.99-4.02 (m, 2H), 4.20 (t,J=5.6 Hz, 2H), 4.29-4.32 (m, 2H), 6.76 (d, J=0.7 Hz, 1H), 6.79 (dd,J=2.3, 0.9 Hz, 1H), 6.86-6.94 (m, 3H), 7.22-7.28 (m, 2H), 7.47 (d, J=2.3Hz, 1H). MS (ES⁺) m/z: 412 (M+H).

Example 26

5-Acetyl-6-(2-methyl-piperazin-1-yl)-4-methyl-7-(3-phenylpropoxy)-benzofuran

Example 20a) (100 mg, 0.23 mmol) and N-methylpiperazine (3 eqs.) werereacted according to General Procedure E. The crude product was purifiedby silica-gel flash chromatography, eluting withmethanol:dichloromethane:ethyl acetate (8:46:46) to afford the titlecompound as a clear oil (78 mg, 75%). ¹H NMR (300 MHz, CDCl₃): δ2.06-2.17 (m, 2H), 2.26 (s, 3H, Me), 2.31 (s, 3H, Me), 2.40-2.55 (bm+s,11H), 2.68 (t, J=5.7 Hz, 2H, CH₂), 2.86 (t, J=7.5 Hz, 2H, CH₂), 4.12 (t,J=5.7 Hz, 2H, CH₂), 4.36 (t, J=6.3 Hz, CH₂), 6.72 (d, J=2.1 Hz, 1H),7.16-7.30 (m, 5H), 7.56 (d, J=2.1 Hz, 1H). MS (ES+) m/z: 451 (M+H⁺).

Example 27

27a) 5-Acetyl-6-(4-bromopropoxy)-4-methyl-7-(3-phenylpropoxy)-benzofuran

Example 18b) (300 mg, 0.93 mmol, 0.8 M), Cs₂CO₃ (2.0 eqs) and1,3-dibromopropane (4 eqs) were reacted according to General ProcedureA. The crude product was purified by flash chromatography, eluting withpetroleum ether:dichloromethane (1:1) to afford the title compound as aclear oil (322 mg, 78%). ¹H NMR (300 MHz, CDCl₃): δ 2.08-2.15 (m, 2H),2.21 (quintet, J=6.3 Hz, 2H), 2.31 (s, 3H, Me), 2.51 (s, 3H, Me), 2.86(t, J=7.5 Hz, 2H, CH₂), 3.55 (t, J=6.6 Hz, 2H), 4.15 (t, J=6.0 Hz, 2H),4.36 (t, J=6.3 Hz, CH₂), 6.73 (d, J=2.1 Hz, 1H), 7.16-7.32 (m, 5H), 7.57(d, J=2.1 Hz, 1H).

27b)5-Acetyl-6-(3-morpholin-4-yl-propoxy)-4-methyl-7-(3-phenylpropoxy)-benzofuran

Example 27a) (150 mg, 0.34 mmol) and morpholine (3 eqs.) were reactedaccording to General Procedure E. The crude product was purified byflash chromatography, eluting with methanol:dichloromethane:ethylacetate (2:49:49) to afford the title compound as a clear oil (131 mg,86%). ¹H NMR (300 MHz, CDCl₃): δ 1.89 (quintet, J=6.3 Hz, 2H), 2.06-2.15(m, 2H), 2.31 (s, 3H, Me), 2.40-2.49 (m, 6H), 2.52 (s, 3H, Me), 2.86 (t,J=7.5 Hz, 2H, CH₂), 3.68 (t, J=4.5 Hz, 2H), 4.07 (t, J=6.0 Hz, 2H), 4.35(t, J=6.3 Hz, CH₂), 6.72 (d, J=2.1 Hz, 1H), 7.15-7.30 (m, 5H), 7.56 (d,J=2.1 Hz, 1H). MS (ES⁺) m/z: 452 (M+H⁺).

Example 28

28a) 5-Acetyl-6-(4-bromobutoxy)-4-methyl-7-(3-phenylpropoxy)-benzofuran

Example 18b) (324 mg, 1.00 mmol, 0.8 M), Cs₂CO₃ (2.0 eqs) and1,3-dibromobutane (4 eqs) were reacted according to General Procedure A.The crude product was purified by flash chromatography, eluting withpetroleum ether:dichloromethane (1:1) to afford the title compound as aclear oil (344 mg, 75%). ¹H NMR (300 MHz, CDCl₃): δ 1.80-1.89 (m, 2H),1.97-2.16 (m, 4H), 2.31 (s, 3H, Me), 2.51 (s, 3H, Me), 2.86 (t, J=7.5Hz, 2H, CH₂), 3.45 (t, J=6.6 Hz, 2H), 4.03 (t, J=6.0 Hz, 2H), 4.35 (t,J=6.3 Hz, CH₂), 6.72 (d, J=2.1 Hz, 1H), 7.16-7.31 (m, 5H), 7.56 (d,J=2.1 Hz, 1H).

28b)5-Acetyl-6-(4-morpholin-4-yl-butoxy)-4-methyl-7-(3-phenylpropoxy)-benzofuran

Example 28a) (160 mg, 0.35 mmol) and morpholine (3 eqs.) were reactedaccording to General Procedure E. The crude product was purified byflash chromatography, eluting with methanol:dichloromethane:ethylacetate (2:49:49) to afford the title compound as a clear oil (95 mg,58%). ¹H NMR (300 MHz, CDCl₃): δ 1.55-1.64 (m, 2H), 1.69-1.78 (m, 2H),2.05-2.15 (m, 2H), 2.31 (s, 3H, Me), 2.32-2.38 (m, 6H), 2.52 (s, 3H,Me), 2.86 (t, J=7.5 Hz, 2H, CH₂), 3.67 (t, J=4.5 Hz, 2H), 4.02 (t, J=6.6Hz, 2H), 4.34 (t, J=6.3 Hz, CH₂), 6.72 (d, J=2.1 Hz, 1H), 7.15-7.30 (m,5H), 7.56 (d, J=2.1 Hz, 1H). MS (ES⁺) m/z: 466 (M+H⁺).

Example 29

5-Acetyl-6-(3-imidazol-1-yl-propoxy)-4-methyl-7-(3-phenylpropoxy)-benzofuran

Example 27a) (100 mg, 0.22 mmol) and imidazole (4 eqs) were reactedaccording to General Procedure E. The crude product was purified byflash chromatography, eluting with methanol:dichloromethane:ethylacetate (4:48:48) to afford the title compound as a clear oil (73 mg,75%). ¹H NMR (300 MHz, CDCl₃): δ 2.04-2.16 (m, 4H), 2.31 (s, 3H, Me),2.52 (s, 3H, Me), 2.83 (t, J=7.5 Hz, 2H, CH₂), 4.04 (t, J=6.3 Hz, 2H),4.09 (t, J=6.6 Hz, 2H), 4.36 (t, J=6.3 Hz, CH₂), 6.73 (d, J=2.1 Hz, 1H),6.93 (bs, 1H), 7.03 (bs, 1H), 7.18-7.29 (m, 5H), 7.57 (bs, 1H), 7.58 (d,J=2.1 Hz, 1H). MS (ES⁺) m/z: 433 (M+H⁺).

Example 30

5-Acetyl-6-(4-imidazol-1-yl-butoxy)-4-methyl-7-(3-phenylpropoxy)-benzofuran

Example 28a) (100 mg, 0.22 mmol) and imidazole (4 eqs) were reactedaccording to General Procedure E. The crude product was purified byflash chromatography, eluting with methanol:dichloromethane:ethylacetate (4:48:48) to afford the title compound as a clear oil (73 mg,75%). ¹H NMR (300 MHz, CDCl₃): δ 1.62-1.71 (m, 2H), 1.86-1.96 (m, 2H),2.04-2.13 (m, 2H), 2.30 (s, 3H, Me), 2.49 (s, 3H, Me), 2.84 (t, J=7.5Hz, 2H, CH₂), 3.95 (t, J=6.3 Hz, 2H), 4.01 (t, J=6.6 Hz, 2H), 4.34 (t,J=6.3 Hz, CH₂), 6.72 (d, J=2.1 Hz, 1H), 6.91 (bs, 1H), 7.04 (bs, 1H),7.15-7.30 (m, 5H), 7.46 (bs, 1H), 7.56 (d, J=2.1 Hz, 1H). MS (ES⁺) m/z:447 (M+H⁺).

Example 31

31a)1-[6-(2-Hydroxy-ethoxy)-4-methyl-7-(3-phenyl-propoxy)-benzofuran-5-yl]-ethanone

Example 31a) was prepared from example 18b) and 2-bromoethanol (2 eq.)as described in General Procedure A in 76% yield. ¹H NMR (300 MHz,CDCl₃): δ 2.08-2.17 (m, 2H), 2.32 (s, 3H), 2.55 (s, 3H), 2.83-2.88 (m,3H), 3.74-3.78 (m, 2H), 4.15-4.17 (m, 2H), 4.39 (t, J=6.4 Hz, 2H), 6.74(d, J=2.1 Hz, 1H), 7.15-7.30 (m, 5H), 7.58 (d, J=2.1 Hz, 1H) MS (ES⁺)m/z 369.0 (M+H⁺).

31b)1-{4-Methyl-7-(3-phenyl-propoxy)-6-[2-(pyrazin-2-yloxy)-ethoxy]-benzofuran-5-yl}-ethanone

To a solution of Example 31a) (120 mg, 0.326 mmol) in dry DMF (2.5 ml)was added sodium hydride (14 mg, 0.359 mmol, 60% dispersion in mineraloil) and the dark reaction mixture was allowed to stir at rt for 30minutes. After this time chloropyrazine (34 ul, 0.39 mmol) was added andthe reaction heated to 80-90° C. overnight then cooled to roomtemperature, quenched with water (20 ml) and extracted with EtOAc (20ml). The organic layer was washed with water (2×20 ml) and brine (20ml), dried over MgSO₄ and concentrated under vacuum. The crude residuewas purified by silica-gel flash chromatography (eluent=4:1hexanes:EtOAc) to provide the product as a clear oil (65 mg, 45%). ¹HNMR (300 MHz, CDCl₃): δ 2.05-2.14 (m, 2H), 2.31 (s, 3H), 2.53 (s, 3H),2.85 (t, J=7.4 Hz, 2H), 4.35-4.41 (m, 4H), 4.56-4.59 (m, 2H), 6.74 (d,J=2.2 Hz, 1H), 7.15-7.30 (m, 5H), 7.58 (d, J=2.2 Hz, 1H), 8.04 (br s,1H), 8.10 (br s, 1H), 8.24 (s, 1H), MS (ES⁺) m/z 446.9 (M+H⁺).

Example 32

1-[6-(2-Cyclopentylamino-ethoxy)-4-methyl-7-(3-phenyl-propoxy)-benzofuran-5-yl]-ethanone

Example 20a) and cyclopentylamine were reacted according to GeneralProcedure E to afford Example 32 in 87% yield. ¹H NMR (300 MHz, CDCl₃):δ 1.29-1.37 (m, 2H), 1.45-1.70 (m, 5H), 1.77-1.85 (m, 2H), 2.07-2.16 (m,2H), 2.31 (s, 3H), 2.53 (s, 3H), 2.82-2.88 (m, 4H), 3.09 (quintet, J=6.6Hz, 1H), 4.14 (t, J=5.2 Hz, 2H), 4.35 (t, J=6.4 Hz, 2H), 6.72 (d, J=1.5Hz, 1H), 7.17-7.30 (m, 5H), 7.56 (d, J=1.5 Hz, 1H) MS (ES⁺) m/z 436.0(M+H⁺).

Example 33

1-[4-Methyl-7-(3-phenyl-propoxy)-6-(2-piperidin-1-yl-ethoxy)-benzofuran-5-yl]-ethanone

Example 20a) and piperidine were reacted according to General ProcedureE to afford Example 33 in 74% yield. ¹H NMR (300 MHz, CDCl₃): δ1.40-1.44 (m, 2H), 1.55 (br m, 4H), 2.07-2.16 (m, 2H), 2.31 (s, 3H),2.43 (br m, 4H), 2.55 (s, 3H), 2.66 (t, J=5.9 Hz, 2H), 2.86 (t, J=7.3Hz, 2H), 4.13 (t, J=6.0 Hz, 2H), 4.35 (t, J=6.4 Hz, 2H), 6.72 (d, J=2.1Hz, 1H), 7.17-7.30 (m, 5H), 7.56 (d, J=2.1 Hz, 1H), MS (ES⁺) m/z 436.0(M+H⁺).

Example 34

1-[4-Methyl-7-(3-phenyl-propoxy)-6-(2-pyrrolidin-1-yl-ethoxy)-benzofuran-5-yl]-ethanone

Example 20a) and pyrrolidine were reacted according to General ProcedureE to afford Example 34 in 67% yield.

¹H NMR (300 MHz, CDCl₃): δ 1.77 (br m, 4H), 2.07-2.16 (m, 2H), 2.31 (s,3H), 2.54 (s, 3H), 2.56 (br m, 4H), 2.79-2.88 (m, 4H), 4.14 (t, J=6.1Hz, 2H), 4.36 (t, J=6.4 Hz, 2H), 6.73 (d, J=2.1 Hz, 1H), 7.15-7.30 (m,5H), 7.56 (d, J=2.1 Hz, 1H), MS (ES⁺) m/z 422.0 (M+H⁺).

Examples 35 and 36

Example 351-[4-Methyl-7-(3-phenyl-propoxy)-6-(2-[1,2,3]triazol-2-yl-ethoxy)-benzofuran-5-yl]ethanoneExample 361-[4-Methyl-7-(3-phenyl-propoxy)-6-(2-[1,2,3]triazol-1-yl-ethoxy)-benzofuran-5-yl]-ethanone

To a suspension of Example 20a) (80 mg, 0.186 mmol) and Cs₂CO₃ (2 eq.)in dry DMF (1.5 ml) was added 1,2,3-triazole (2.5 eq.) and the reactionwas stirred at 90° C. overnight. After cooling the reaction was quenchedwith water (20 ml) and extracted with EtOAc (20 ml). The organic layerwas washed with water (2×20 ml) and brine (20 ml), dried over MgSO₄ andconcentrated under vacuum. The crude residue was subjected to silica-gelflash chromatography (eluent=DCM then 19:1 DCM:EtOAc to give Example 35as a clear oil (38 mg, 49%). ¹H NMR (300 MHz, CDCl₃): δ 2.03-2.15 (m,2H), 2.30 (s, 3H), 2.37 (s, 3H), 2.83 (t, J=7.2 Hz, 2H), 4.30 (t, J=6.4Hz, 2H), 4.53-4.57 (m, 2H), 4.77-4.80 (m, 2H), 6.74 (d, J=2.2 Hz, 1H),7.18-7.33 (m, 5H), 7.59 (d, J=2.2 Hz, 1H), 7.63 (s, 2H), MS (ES⁺) m/z419.9 (M+H⁺).

Further elution (eluent=4:1 DCM:EtOAc) provided Example 36 as a clearoil (33 mg, 42%). ¹H NMR (300 MHz, CDCl₃): δ 2.00-2.09 (m, 2H), 2.32 (s,3H), 2.37 (s, 3H), 2.80 (t, J=7.3 Hz, 2H), 4.30 (t, J=6.5 Hz, 2H),4.44-4.47 (m, 2H), 4.69-4.72 (m, 2H), 6.75 (d, J=2.2 Hz, 1H), 7.16-7.33(m, 5H), 7.60 (d, J=2.2 Hz, 1H), 7.72 (s, 1H), 7.74 (s, 1H). MS (ES⁺)m/z 419.9 (M+H⁺).

Example 37

1-[4-Methyl-7-(3-phenyl-propoxy)-6-(2-[1,2,4]triazol-1-yl-ethoxy)-benzofuran-5-yl]-ethanone

Example 37 was prepared in the same manner as described for Example 36but from 1,2,4-triazole in 84% yield. ¹H NMR (300 MHz, CDCl₃): δ2.02-2.11 (m, 2H), 2.32 (s, 3H), 2.38 (s, 3H), 2.81 (t, J=7.4 Hz, 2H),4.30 (t, J=6.5 Hz, 2H), 4.41-4.47 (m, 4H), 6.75 (d, J=2.2 Hz, 1H),7.18-7.33 (m, 5H), 7.60 (d, J=2.2 Hz, 1H), 7.96 (s, 1H), 8.21 (s, 1H).MS (ES⁺) m/z 419.9 (M+H⁺).

Example 38

4-{2-[5-Acetyl-4-methyl-7-(3-phenyl-propoxy)-benzofuran-6-yloxy]-ethyl}-morpholin-3-one

A solution of Example 20 (55 mg, 0.17 mmol) in MeCN (1.0 mL) was addedto CsCO₃ (110 mg, 0.34 mmol), tetrabutylammonium bromide (3 mg, 0.009mmol) and morpholin-3-one (17 mg, 0.17 mmol) and the reaction mixturewas stirred at 60° C. for 48 h, then diluted with DCM and filtered,washing with DCM. The solvent was concentrated under vacuum. The crudeproduct was subjected to silica-gel flash chromatography (petroleumether/ethyl acetate, 9:1, 7:3) to give Example 38 (4 mg, 5%). ¹H NMR(300 MHz, CDCl₃): δ 2.01-2.15 (m, 2H), 2.30 (s, 3H), 2.49 (s, 3H),2.81-2.87 (m, 2H), 3.48 (t, J=5.3 Hz, 2H), 3.72 (t, J=5.3 Hz, 2H),3.87-3.89 (m, 2H), 4.41-4.17 (m, 2H), 4.22 (t, J=5.0 Hz, 2H), 4.33-4.41(m, 2H), 6.72 (d, J=2.2 Hz, 1H), 7.15-7.35 (m, 5H), 7.57 (d, J=2.2 Hz,1H). MS (ES⁺) m/z 452.2 (M+H⁺).

Example 39

5-Acetyl-6-(2-(2-Hydroxy-ethylamino)-ethoxy)-4-methyl-7-(3-phenylpropoxy)-benzofuran

Example 20a) (344 mg, 0.80 mmol) and 2-aminoethanol (2.5 eqs.) werereacted according to General Procedure E, except the reaction time was15 hours. The crude product was purified by flash chromatography,eluting with methanol:dichloromethane (1:5) to afford the title compoundas a dark brownish oil (138 mg, 42%). ¹H NMR (300 MHz, CDCl₃): δ2.06-2.16 (m, 2H), 2.31 (s, 3H), 2.53 (s, 3H), 2.74-2.87 (bm, 6H), 2.95(t, J=4.9 Hz, 2H), 3.67 (t, J=5.1 Hz, 2H), 4.20 (t, J=4.9 Hz, 2H), 4.4(t, J=6.5 Hz, 2H), 6.72 (d, J=2.1 Hz, 1H), 7.14-7.29 (m, 5H), 7.57 (d,J=2.1 Hz, 1H). MS (ES⁺) m/z 412 (M+H⁺).

Example 40

5-Acetyl-4-methyl-7-(3-phenylpropoxy)-6-(2-pyridin-2-yl-ethoxy)benzofuran

Example 18b) (324 mg, 1.00 mmol, 0.1 M), Cs₂CO₃ (2 eqs) and2-pyridin-2-ylethyl methanesulfonate (3 eqs) were reacted according toGeneral Procedure A. The crude residue was subjected to flashchromatography, eluting with ethylacetate:dichloromethane (1:4) toafford the title compound as a yellow oil (248 mg, 58%). ¹H-NMR (300MHz, CDCl₃) δ 1.99-2.09 (m, 2H), 2.28 (s, 3H), 2.32 (s, 3H), 2.81 (t,J=7.8 Hz, 2H), 3.18 (t, J=6.5 Hz, 2H), 4.27 (t, J=6.3 Hz, 2H), 4.44 (t,J=6.5 Hz, 2H), 6.71 (d, J=2.1 Hz, 1H), 7.07-7.29 (m, 7H), 7.55-7.59 (m,2H), 8.52 (d, J=3.9 Hz, 1H). MS (ES⁺) m/z 429.9 (M+H⁺).

Example 41

1-[2-Chloro-4-methyl-6-(2-morpholin-4-yl-ethoxy)-7-(3-phenyl-propoxy)-benzofuran-5-yl]-ethanone

To a solution of Example 20a) (120 mg, 0.278 mmol) in dry DMF (1.5 ml)was added N-chlorosuccinimide (74 mg, 0.554 mmol) and the reaction wasstirred at 75° C. for 3 h. After cooling the reaction was quenched with10% Na₂S₂O_(3 (aq)) (20 ml) and extracted with EtOAc (20 ml). Theorganic layer was washed with water (20 ml) and brine (20 ml), driedover MgSO₄ and concentrated under vacuum. The residue was subjected tosilica-gel flash chromatography (eluent=5% EtOAc in hexanes) to providethe crude 2-chloro derivative (˜45 mg), which was dissolved in dry DMF(1.5 ml) and treated with excess morpholine (50 ul). After stirring at70° C. overnight the reaction was cooled, quenched with water (20 ml)and extracted with EtOAc (20 ml). The organic layer was washed withbrine (20 ml), dried over MgSO₄ and concentrated under vacuum. The cruderesidue was purified by silica-gel flash chromatography (eluent=15%EtOAc in DCM) to provide the product as a clear oil (23 mg, 18% over 2steps). ¹H NMR (300 MHz, CDCl₃): δ 2.06-2.15 (m, 2H), 2.25 (s, 3H),2.47-2.50 (m, 4H), 2.54 (s, 3H), 2.66 (t, J=5.6 Hz, 2H), 2.86 (t, J=7.4Hz, 2H), 3.67-3.70 (m, 4H), 4.11 (t, J=5.6 Hz, 2H), 4.33 (t, J=6.3 Hz,2H), 6.54 (s, 1H), 7.16-7.31 (m, 5H). MS (ES⁺) m/z 471.9 (M+H⁺).

Example 42

2-[5-Acetyl-4-methyl-7-(3-phenyl-propoxy)-benzofuran-6-yloxy]-1-morpholin-4-yl-ethanone

Example 18b) (39 mg, 0.12 mmol) was reacted with2-chloro-1-morpholin-4-yl-ethanone (23 mg, 0.14 mmol) as described underGeneral Procedure A and the crude residue was purified by silica-gelflash chromatography (petroleum ether/ethyl acetate, 9:1) to provide thetitle compound (41 mg, 76%). ¹H NMR (300 MHz, CDCl₃): δ 2.02-2.15 (m,2H), 2.31 (s, 3H), 2.56 (s, 3H), 2.80-2.85 (m, 2H), 3.44-3.62 (m, 8H),4.38 (t, J=6.5 Hz, 2H), 4.71 (s, 2H), 6.74 (d, J=2.2 Hz, 1H), 7.17-7.27(m, 5H), 7.57 (d, J=2.2 Hz, 1H). MS (ES⁺) m/z 452.2 (M+H⁺).

Example 43 Step i

43a) 9-Hydroxy-4,7-dimethyl-furo[3,2-g]chromen-5-one

The title compound was prepared by treatment of Example 4a) with BBr₃according to General Procedure D in 78% yield. ¹H NMR (300 MHz,DMSO-d6): δ 2.33 (s, 3H, CH₃), 2.79 (s, 3H, CH₃), 6.02 (s, 1H), 7.13 (d,J=2.1 Hz, 1H), 8.02 (d, J=2.1 Hz, 1H), 10.29 (s, 1H, OH).

Step ii

43b)9-[2-(4-Fluoro-phenoxy)-ethoxy]-4,7-dimethyl-furo[3,2-g]chromen-5-one

Example 43a) was treated with 1-(2-bromoethoxy)-4-fluorobenzeneaccording to General Procedure A. The crude residue was subjected toflash chromatography, eluting with ethylacetate:dichloromethane (1:9) toafford the title compound in 67% yield. ¹H NMR (300 MHz, CDCl₃): δ 2.25(s, 3H, CH₃), 2.97 (s, 3H, CH₃), 4.31 (t, J=4.5, 2H), 4.70 (t, J=4.5,2H), 6.02 (s, 1H), 6.78-6.98 (m, 5H), 7.63 (d, J=2.1 Hz, 1H).

Step iii

43c)5-Acetyl-7-(2-(4-fluorophenoxy)-ethoxy)-6-hydroxy-4-methylbenzofuran

The title compound was prepared from Example 43b) as described underGeneral Procedure B and the crude residue was subjected to flashchromatography, eluting with ethylacetate:dichloromethane (1:19) toafford the title compound in 55% yield. ¹H NMR (300 MHz, CDCl₃): δ 2.47(s, 3H, CH₃), 2.60 (s, 3H, CH₃), 4.24 (t, J=4.5, 2H), 4.60 (t, J=4.5,2H), 6.73 (d, J=2.1 Hz, 1H), 6.84-6.99 (m, 4H), 7.51 (d, J=2.1 Hz, 1H),8.39 (s, 1H). MS (ES⁺) m/z 344.9 (M+H⁺).

Step iv

43d)5-Acetyl-6-(2-bromoethoxy)-7-(2-(4-fluorophenoxy)-ethoxy)-4-methylbenzofuran

The title compound was prepared by reacting Example 43c) with1,2-dibromoethane (4 eq.) as described under General Procedure A and thecrude residue was subjected to flash chromatography, eluting withhexane:dichloromethane (2:1, 1:1, 1:0) to afford the title compound in72% yield. ¹H NMR (300 MHz, CDCl₃): δ 2.32 (s, 3H, CH₃), 2.53 (s, 3H,CH₃), 3.53 (t, J=6.3 Hz, 2H), 4.29 (t, J=4.5, 2H), 4.35 (t J=6.3 Hz,2H), 4.68 (t, J=4.2, 2H), 6.75 (d, J=2.1 Hz, 1H), 6.83-6.99 (m, 4H),7.58 (d, J=2.1 Hz, 1H). MS (ES⁺) m/z 450.8, 452.8 (M+H⁺).

Step v

43e)1-[7-[2-(4-Fluoro-phenoxy)-ethoxy]-4-methyl-6-(2-morpholin-4-yl-ethoxy)-benzofuran-5-yl]-ethanone

Example 43e) was prepared from 43 d) and morpholine as described underGeneral Procedure E in 90% yield. ¹H NMR (300 MHz, CDCl₃): δ 2.31 (s,3H), 2.44-2.47 (m, 4H), 2.55 (s, 3H), 2.64 (t, J=5.6 Hz, 2H), 3.64-3.67(m, 4H), 4.16 (t, J=5.6 Hz, 2H), 4.26-4.29 (m, 2H), 4.66-4.70 (m, 2H),6.74 (d, J=2.2 Hz, 1H), 6.83-6.88 (m, 2H), 6.92-6.99 (m, 2H), 7.57 (d,J=2.2 Hz, 1H). MS (ES⁺) m/z 457.9 (M+H⁺).

Example 44

44a) 1-(3-Bromo-1-methyl-propyl)-4-fluorobenzene

A solution of ethyl 3-(4-fluorophenyl)butanoate (2.85 g, 13.6 mmol) inTHF (10 mL) was added to a solution of lithium aluminum hydride (0.77 g,1.5 mmol) in THF (60 mL) at 0° C. The reaction was stirred at roomtemperature overnight, then cooled to 0° C., quenched with NH₄Cl_((aq))(sat., 50 mL) and extracted with EtOAc (3×100 mL). The pooled organicswere washed with brine (100 mL), dried (Na₂SO₄) and concentrated undervacuum to give the alcohol, which was used directly in the next step.Bromine (1.03 mL, 20.0 mmol) was added dropwise to a solution oftriphenylphosphine (5.24 g, 20.0 mmol) in DCM (80 mL) at 0° C. until anorange colour persisted. The reaction mixture was stirred at roomtemperature for 90 min, then a solution of the alcohol (2.37 g, 14.1mmol) in DCM (20 mL) was added and the reaction mixture stirredovernight. The reaction mixture was concentrated under vacuum and theresulting residue was sonicated for 5 min in petroleum ether (100 mL).The suspension was filtered, and the white solid washed with petroleumspirit. The washings were concentrated under vacuum to give the titlecompound (2.56 g, 81% over 2 steps) as a colourless oil. ¹H-NMR (300MHz, CDCl₃) δ 1.31 (d, J=6.9 Hz, 3H), 2.08-2.15 (m, 2H), 2.92-3.00 (m,1H), 3.15-3.20 (m, 1H), 3.31-3.36 (m, 1H), 7.18-7.26 (m, 2H)

44b)9-[3-(4-Fluoro-phenyl)-butoxy]-4,7-dimethyl-furo[3,2-g]chromen-5-one

The example 43a) (400 mg, 1.74 mmol) and 44a) (1.2 eqs) were reactedaccording to General Procedure A and the crude was purified by flashchromatography eluting with ethylacetate:hexane (2:8) to offer the titlecompound (540 mg, 82%) as white solid. ¹H-NMR (300 MHz, CDCl₃) δ 1.31(d, J=6.9 Hz, 3H), 1.98-2.15 (m, 2H), 2.34 (s, 3H), 2.94 (s, 3H),3.11-3.18 (m, 1H), 4.15-4.33 (m, 2H), 6.04 (s, 1H), 6.90-6.99 (m, 3H),7.16-7.20 (m, 2H), 7.62 (d, J=2.1 Hz, 1H). MS (ES⁺) m/z 380.9 (M+H⁺).

44c) 5-Acetyl-7-(3-(4-fluorophenyl)butoxy)-6-hydroxy-4-methylbenzofuran

Example 44b) (540 mg, 1.42 mmol) was hydrolysed according to GeneralProcedure B and the crude was purified with flash silica gel columnchromatography eluting with ethylacetate:hexane (1:9) to offer the titlecompound (260 mg, 51%) as yellow oil. ¹H-NMR (300 MHz, CDCl₃) δ 1.29 (d,J=6.9 Hz, 3H), 1.93-2.14 (m, 2H), 2.52 (s, 3H), 2.63 (s, 3H), 2.99-3.11(m, 1H), 4.14-4.28 (m, 2H), 6.71 (d, J=2.1 Hz, 1H), 6.92-6.98 (m, 2H),7.15-7.19 (m, 2H), 7.47 (d, J=2.1 Hz, 1H), 9.16 (s, 1H). MS (ES⁺) m/z356.9 (M+H⁺).

44d)5-Acetyl-7-(3-[4-fluorophenyl]butoxy)-4-methyl-6-(2-pyridin-2-yl-ethoxy)benzofuran

A suspension of Example 44c) (60 mg, 0.17 mmol, 0.2 M), Cs₂CO₃ (109 mg,0.33 mmol) and 2-pyridin-2-ylethyl methanesulfonate (51 mg, 0.25 mmol)were heated in anhydrous DMF at 60-70° C. under inert atmosphere. After2 h additional amounts of Cs₂CO₃ (33 mg, 0.10 mmol) and2-pyridin-2-ylethyl methanesulfonate (20 mg, 0.10 mmol) were added andreaction continued for 20 minutes. Then solvents were removed undervacuum and the residue was dissolved in EtOAc (25 mL) and washed withNH₄Cl (aq) (20 mL), water (20 mL) and brine (20 mL). The organic layerwas dried (MgSO₄) and evaporated. The crude was purified by flashsilica-gel chromatography eluting with ethylacetate:dichloromethane(1:9) to afford the title compound as a yellow oil (53 mg, 68%). ¹H-NMR(300 MHz, CDCl₃) δ 1.26 (d, J=6.9 Hz, 3H), 1.86-2.10 (m, 2H), 2.26 (s,3H), 2.32 (s, 3H), 2.96-3.08 (m, 1H), 3.16 (t, J=6.5 Hz, 2H), 4.06-4.22(m, 2H), 4.40 (t, J=6.5 Hz, 2H), 6.69 (d, J=2.1 Hz, 1H), 6.89-6.97 (m,2H), 7.09-7.23 (m, 4H), 7.52 (d, J=2.1 Hz, 1H), 7.60 (dt, J=1.7 Hz, 7.6Hz, 1H), 8.52 (d, J=4.3 Hz, 1H). MS (ES⁺) m/z 461.9 (M+H⁺).

Example 45

45a)5-Acetyl-6-(2-bromoethoxy)-7-(3-(4-fluorophenyl)butoxy)-4-methylbenzofuran

Example 44c) (200 mg, 0.56 mmol), 1,2-dibromoethane (6.0 eqs) and Cs₂CO₃(1.3 eqs) were heated in anhydrous DMF (2 ml) at 60° C. for 1 h and anadditional amount of Cs₂CO₃ (0.4 eqs) was added and stirring continuedfor another 30 min. The reaction mixture was then diluted with ethylacetate and washed twice with 10% citric acid and then brine, dried overMgSO₄, and concentrated in vacuo. The excess of 1,2-dibromoethane wasremoved under high vacuum at 50° C. to offer the title compound (260 mg,100%) as clear oil. ¹H-NMR (300 MHz, CDCl₃) δ 1.29 (d, J=6.9 Hz, 3H),1.93-2.13 (m, 2H), 2.30 (s, 3H), 2.53 (s, 3H), 3.04-3.11 (m, 1H), 3.53(t, J=6.2 Hz, 2H), 4.16-4.30 (m, 4H), 6.72 (d, J=2.1 Hz, 1H), 6.93-6.99(m, 2H), 7.15-7.20 (m, 2H), 7.55 (d, J=2.1 Hz, 1H). MS (ES⁺) m/z 462.8,464.8 (M+H⁺).

45b)5-Acetyl-7-(3-[4-fluorophenyl]butoxy)-4-methyl-6-(2-Cyclopentylamino-ethoxy)benzofuran

Example 45a) (170 mg, 0.37 mmol, 0.2 M) and cyclopentylamine were heatedin anhydrous DMF at 60-70° C. under inert atmosphere for 6 h. Thereaction was cooled, quenched by addition of water and extracted withethyl acetate. The organic layer was washed with brine, dried over MgSO₄and evaporated. The crude mixture was purified by flash chromatographyeluting with ethyl acetate:dichloromethane (1:2) to offer the titlecompound (145 mg, 84%) as a clear oil. ¹H-NMR (300 MHz, CDCl₃) δ1.28-1.36 (m, 5H), 1.50-1.70 (m, 5H), 1.77-1.86 (m, 2H), 2.02-2.14 (m,2H), 2.29 (s, 3H), 2.51 (s, 3H), 2.85 (t, J=5.2 Hz, 2H), 3.02-3.13 (m,2H), 4.10 (t, J=5.2 Hz, 2H), 4.17-4.28 (m, 2H), 6.71 (d, J=2.1 Hz, 1H),6.92-6.98 (m, 2H), 7.15-7.20 (m, 2H), 7.52 (d, J=2.1 Hz, 1H). MS (ES⁺)m/z 468 (M+H⁺).

Example 46

46a) 4,7-Dimethyl-9-(3-methyl-3-phenyl-butoxy)-furo[3,2-g]chromen-5-one

Example 46a) was prepared by reacting Example 43a) with4-bromo-1-methyl-1-phenyl-butane (prepared by triphenylphosphine/brominebromination of the known precursor alcohol—Zhurnal Organicheskoi Khimii,24 (8), p 1610, 1988) as described in General Procedure A in 49% yield.

46b)rac-1-[4-Methyl-7-(3-methyl-3-phenyl-butoxy)-6-(2-morpholin-4-yl-ethoxy)-benzofuran-5-yl]ethanone

The title compound was prepared from Example 46a) in 39% yield overthree steps in the same manner as described for Example 43 Steps iii-v.¹H NMR (300 MHz, CDCl₃: δ 1.39 (s, 6H), 2.20 (t, J=7.6 Hz, 2H), 2.28 (s,3H), 2.47-2.50 (m, 4H), 2.52 (s, 3H), 2.63 (t, J=5.6 Hz, 2H), 3.69-3.72(m, 4H), 4.04 (t, J=5.6 Hz, 2H), 4.16 (t, J=7.6 Hz, 2H), 6.69 (m, 1H),7.14-7.19 (m, 1H), 7.24-7.37 (m, 4H), 7.51 (m, 1H). MS (ES⁺) m/z 466.0(M+H⁺).

Example 47

47a) 5-Acetyl-7-(3-(4-fluorophenyl)propoxy)-6-hydroxy-4-methylbenzofuran

4,9-Dihydroxy-7-methyl-5H-furo[3,2-g]chromen-5-one was reacted with1-bromo-3-(4-fluorophenyl)propane according to General Procedure A togive9-(3-[4-fluorophenyl]propoxy)-4-hydroxy-5H-furo[3,2-g]chromen-5-one,that was further reacted according to General Procedure G step 1-3, toprovide the title compound in 22% yield (over 4 steps). ¹H NMR (300 MHz,CDCl₃): δ 2.04-2.14 (m, 2H), 2.53 (s, 3H, CH₃), 2.63 (s, 3H, CH₃), 2.83(t, J=7.8, 2H), 4.34 (t, J=6.3, 2H), 6.73 (d, J=2.1, 1H), 6.94 (t J=8.7Hz, 2H), 7.13-7.18 (m, 2H), 7.50 (d, J=2.1 Hz, 1H), 8.98 (s, 1H, OH). MS(ES) m/z: 342.9 (M+H⁺).

47b)5-Acetyl-7-(3-(4-fluorophenyl)propoxy)-4-methyl-6-(2-morpholinoethoxy)benzofuran

The title compound was prepared from Example 47a) as described inExample 43 step iv, v in 60% yield. ¹H-NMR (300 MHz, CDCl₃) δ 2.04-2.13(m, 2H), 2.31 (s, 3H), 2.49 (t J=4.2 Hz, 4H), 2.55 (s, 3H), 2.67 (t,J=5.6 Hz, 2H), 2.84 (t, J=7.3 Hz, 2H), 3.69 (t, J=4.7 Hz, 4H), 4.13 (t,J=5.7 Hz, 2H), 4.34 (t, J=6.3 Hz, 2H), 6.73 (d, J=2.1 Hz, 1H), 6.95 (t,J=8.7 Hz, 1H), 7.14-7.19 (m, 2H), 7.56 (d, J=2.1 Hz, 1H). MS (ES⁺) m/z455.9 (M+H⁺).

Example 48

1-[6-(2-Cyclopentylamino-ethoxy)-4-methyl-7-(3-(4-fluoro-phenyl)-propoxy)-benzofuran-5-yl]-ethanone

The title compound was prepared in 2 steps from Example 47a) in 89%yield in the same manner as described for Example 43 Steps iv-v. ¹H NMR(300 MHz, CDCl₃): δ 1.28-1.35 (m, 2H), 1.49-1.56 (m, 2H), 1.61-1.70 (m,2H), 1.79-1.85 (m, 2H), 2.03-2.12 (m, 2H), 2.31 (s, 3H), 2.53 (s, 3H),2.80-2.89 (m, 4H), 3.09 (quintet, J=6.5 Hz, 1H), 4.14 (t, J=5.2 Hz, 2H),4.33 (t, J=6.4 Hz, 2H), 6.73 (d, J=2.2 Hz, 1H), 6.92-6.98 (m, 2H),7.14-7.19 (m, 2H), 7.56 (d, J=2.2 Hz, 1H). MS (ES⁺) m/z 454.0 (M+H⁺).

Example 49

1-[7-[3-(4-Fluoro-phenyl)-propoxy]-4-methyl-6-(2-pyridin-2-yl-ethoxy)-benzofuran-5-yl]-ethanone

The title compound was prepared from Example 47a) and2-pyridin-2-ylethyl methanesulfonate in 61% yield as described inGeneral Procedure A. ¹H NMR (300 MHz, CDCl₃): δ 1.96-2.06 (m, 2H), 2.28(s, 3H), 2.33 (s, 3H), 2.78 (t, J=7.4 Hz, 2H), 3.18 (t, J=6.6 Hz, 2H),4.25 (t, J=6.3 Hz, 2H), 4.44 (t, J=6.6 Hz, 2H), 6.71 (d, J=2.2 Hz, 1H),6.90-6.97 (m, 2H), 7.08-7.23 (m, 4H), 7.55-7.60 (m, 2H), 8.51 (d, J=4.8Hz, 1H). MS (ES⁺) m/z 447.9 (M+H⁺).

Example 50

50a)1-[6-Hydroxy-4-methyl-7-(3-RS-phenylbutoxy)-benzofuran-5-yl]-ethanone

To a suspension of Example 43a) (92 mg, 0.40 mmol) indichloromethane/tetrahydrofuran (1:1, 4 mL) was added polymer-boundtriphenylphosphine (1.0 mmol loading, 600 mg, 0.60 mmol),3-RS-phenylbutan-1-ol (95 μL, 0.65 mmol) and diethylazodicarboxylate (94μL, 0.60 mmol). The reaction mixture was stirred at rt for 16 h thenfiltered through a Celite pad, washing with dichloromethane andtetrahydrofuran. The solvent was concentrated in vacuo and the crudeproduct was purified by flash chromatography eluting with ethylacetate:petroleum ether (1:4) to offer a mixture of the intermediatechromenone and 3-RS-phenyl-butan-1-ol. This mixture was treated asdescribed under General Procedure B to afford the title compound (60 mg,44% yield over 2 steps). ¹H NMR (300 MHz, CDCl₃): δ 1.32 (d, J=7.0 Hz,3H), 2.06-2.13 (m, 2H), 2.53 (s, 3H), 2.65 (s, 3H), 3.01-3.09 (m, 1H),4.22-4.30 (m, 2H), 6.73 (d, J=2.3 Hz, 1H), 7.16-7.32 (m, 5H), 7.49 (d,J=2.3 Hz, 1H), 8.79 (s, 1H).

50b)1-[4-Methyl-6-(2-morpholin-4-yl-ethoxy)-7-(3-phenyl-butoxy)-benzofuran-5-yl]-ethanone

Example 50a) was treated with 4-(2-chloroethyl)morpholine hydrochlorideas described under General Procedure I and the crude product waspurified by flash chromatography with methanol:ethylacetate:dichloromethane (1:29:70) to give the title compound in 79%yield. ¹H-NMR (300 MHz, CDCl₃) δ 1.33 (d, J=7.0 Hz, 3H), 2.03-2.10 (m,2H), 2.29 (s, 3H), 2.47-2.50 (m, 4H), 2.54 (s, 3H), 2.65 (t, J=3.3 Hz,2H), 3.01-3.09 (m, 1H), 3.67-3.71 (m, 4H), 4.10 (t, J=3.4 Hz, 2H),4.21-4.29 (m, 2H), 6.71 (d, J=2.2 Hz, 1H), 7.14-7.25 (m, 5H), 7.53 (d,J=2.2 Hz, 1H).

Example 51

1-[4-Methyl-6-(2-morpholin-4-yl-ethoxy)-7-(3-phenyl-butoxy)-benzofuran-5-yl]-ethanone

Example 43a) and 3-R-phenylbutan-1-ol were treated as described abovefor Example 50a) and 50 b) to give the title compound in 28% yield over3 steps. ¹H-NMR (300 MHz, CDCl₃) δ 1.34 (d, J=7.0 Hz, 3H), 2.05-2.12 (m,2H), 2.31 (s, 3H), 2.48-2.520 (m, 4H), 2.56 (s, 3H), 2.67 (t, J=3.3 Hz,2H), 3.03-3.11 (m, 1H), 3.69-3.73 (m, 4H), 4.11 (t, J=3.4 Hz, 2H),4.22-4.30 (m, 2H), 6.72 (d, J=2.2 Hz, 1H), 7.16-7.31 (m, 5H), 7.53 (d,J=2.2 Hz, 1H).

Example 52

rac-1-[4-Methyl-7-(3-phenyl-butoxy)-6-(2-pyridin-2-yl-ethoxy)-benzofuran-5-yl]-ethanone

The title compound was prepared from Example 50a) and2-pyridin-2-ylethyl methanesulfonate in 64% yield as described inGeneral Procedure A. ¹H NMR (300 MHz, CDCl₃): δ 1.29 (d, J=7.0 Hz, 6H),1.98-2.04 (m, 2H), 2.26 (s, 3H), 2.31 (s, 3H), 2.99-3.06 (m, 1H), 3.16(t, J=6.6 Hz, 2H), 4.10-4.23 (m, 2H), 4.41 (t, J=6.6 Hz, 2H), 6.69 (d,J=2.0 Hz, 1H), 7.09-7.28 (m, 8H), 7.52 (d, J=2.0 Hz, 1H), 7.55-7.60 (m,1H), 8.52 (d, J=4.6 Hz, 1H). MS (ES⁺) m/z 443.9 (M+H⁺).

Example 53

1-[6-(2-Cyclopentylamino-ethoxy)-4-methyl-7-(3-phenyl-butoxy)-benzofuran-5-yl]-ethanone

The title compound was prepared in 2 steps from Example 50a) in 76%yield in the same manner as described for Example 43 Steps iv-v. ¹H NMR(300 MHz, CDCl₃): δ 1.34 (d, J=7.0 Hz, 3H), 1.37-1.42 (m, 2H), 1.52-1.57(m, 2H), 1.68-1.89 (m, 4H), 2.06-2.13 (m, 2H), 2.31 (s, 3H), 2.53 (s,3H), 2.89 (t, J=5.3 Hz, 2H), 3.03-3.16 (m, 2H), 4.16 (t, J=5.3 Hz, 2H),4.22-4.28 (m 2H), 6.72 (d, J=2.2 Hz, 1H), 7.16-7.26 (m, 5H), 7.54 (d,J=2.2 Hz, 1H). MS (ES⁺) m/z 450.3 (M+H⁺).

Example 54

54a) 5-Acetyl-6-(3-cyanopropoxy)-4-methyl-7-(3-phenylpropoxy)benzofuran

A suspension of Example 27a) (445 mg, 1.00 mmol) and NaCN (75 mg, 1.53mmol) in anhydrous DMSO (3 ml) was heated at 65-70° C. overnight underinert atmosphere. The reaction was cooled and quenched by addition ofaqueous NH₄Cl solution and extracted with EtOAc. The organic portion wasdried (MgSO₄), evaporated under vacuum and residue was purified by flashchromatography eluting with dichloromethane yielding (150 mg, 38%) ofthe title compound. ¹H NMR (300 MHz, CDCl₃): δ 1.98-2.18 (m, 4H), 2.30(s, 3H), 2.51 (s, 3H), 2.84 (t, J=7.3 Hz, 2H), 4.09 (t, J=5.8 Hz, 2H),4.37 (t, J=6.5 Hz, 2H), 6.73 (d, J=2.1 Hz, 1H), 7.16-7.30 (m, 5H), 7.57(d, J=2.1 Hz, 1H). MS (ES⁺) m/z 391.9, 408.9 (M+M⁺, NH₄ ⁺).

54b)5-Acetyl-6-(3-(1H-tetrazol-5-yl)-propoxy)-4-methyl-7-(3-phenylpropoxy)benzofuran

Example 54a) (130 mg, 0.33 mmol), TBAF (1.0 eqs) and TMS-N₃ (1.5 eqs)were heated at 110-120° C. for 72 hours in a closed RB Flask. Thereaction mixture was cooled, quenched by addition of aqueous NH₄Cl (20mL) and extracted with EtOAc (20 mL). After evaporation, the crude waspurified by flash chromatography withmethanol:ethylacetate:dichloromethane (5:20:75) to give the titlecompound in 33% yield. ¹H NMR (300 MHz, CDCl₃): δ 2.04-2.14 (m, 4H),2.34 (s, 3H), 2.58 (s, 3H), 2.81 (t, J=8.0 Hz, 2H), 3.12 (t J=6.8 Hz,2H), 4.00 (t, J=5.3 Hz, 2H), 4.40 (t, J=6.5 Hz, 2H), 6.74 (d, J=2.1 Hz,1H), 7.16-7.29 (m, 5H), 7.59 (d, J=2.1 Hz, 1H). MS (ES⁺) m/z 434.9(M+H⁺).

Example 55

5-Acetyl-6-(3-(1H-tetrazol-5-yl)-ethoxy)-4-methyl-7-(3-phenylpropoxy)benzofuran

The title compound was prepared in two steps by reacting Example 20a)with NaCN (0.5 eqs), followed by reaction with TMS-N₃ and TBAF asdescribed in Example 54. Purification of crude give the title compoundin 5% yield (over 2 steps). ¹H NMR (300 MHz, CDCl₃): δ 2.10-2.20 (m,2H), 2.33 (s, 3H), 2.49 (s, 3H), 2.78 (t, J=7.9 Hz, 2H), 3.37 (t J=6.8Hz, 2H), 4.00 (t, J=5.4 Hz, 2H), 4.31 (t, J=5.4 Hz, 2H), 4.53 (t, J=6.7Hz, 2H), 6.75 (d, J=2.1 Hz, 1H), 7.15-7.28 (m, 5H), 7.59 (d, J=2.1 Hz,1H). MS (ES⁺) m/z 420.9 (M+H⁺).

Example 56

56a)5-Acetyl-7-(2,2-dimethyl-3-phenylpropoxy)-4-methyl-6-(2-morpholinoethoxy)benzofuran

Example 43a) (115 mg, 0.50 mmol), 1-bromo-2,2-dimethyl-3-phenylpropane(98.4 mg, 0.60 mmol) and PPh₃ (157 mg, 0.60 mmol) were added toanhydrous THF (0.8 mL) in a Schlenk tube under N₂ atmosphere andsonicated for 10 minutes, and di-tertbutyl azodicarboxylate (138 mg,0.60 mmol) was then added. The reaction mixture was sonicated for 3hours. Additional amount of PPh₃ (80 mg, 0.30 mmol) and di-tertbutylazodicarboxylate (69 mg, 0.30 mmol) were added to the reaction mixtureand sonicated for a further 2 hours. The solvents were removed undervacuum and the residue was chromatographed on silica-gel to give coupledproduct (70 mg, 37%). The isolated product was hydrolysed according toGeneral Procedure B to afford the title compound in 54% yield. ¹H NMR(300 MHz, CDCl₃): δ 1.05 (s, 6H), 2.52 (s, 3H), 2.64 (s, 3H), 2.78 (s,2H), 3.98 (s, 2H), 6.73 (d, J=2.1 Hz, 1H), 7.18-7.29 (m, 5H), 7.50 (d,J=2.1 Hz, 1H), 8.91 (s, 1H). MS (ES⁺) m/z 352.9 (M+H⁺).

56b)5-Acetyl-7-(2,2-dimethyl-3-phenylpropoxy)-4-methyl-6-(2-morpholinoethoxy)benzofuran

The title compound was prepared from Example 56a) as described inExample 43 step iv and v in 64% yield (over 2 steps). ¹H-NMR (300 MHz,CDCl₃) δ 1.05 (s, 6H), 2.31 (s, 3H), 2.48 (t, J=4.5 Hz, 4H), 2.57 (s,3H), 2.67 (t, J=5.7 Hz, 2H), 2.78 (s, 2H), 3.69 (t, J=4.9 Hz, 4H), 4.02(s, 2H), 4.14 (t, J=5.7 Hz, 2H), 6.73 (d, J=2.1 Hz, 1H), 7.16-7.29 (m,5H), 7.57 (d, J=2.1 Hz, 1H). MS (ES⁺) m/z 466.0 (M+H⁺).

Example 57

57a)1-[6-Hydroxy-4-methyl-7-(1-RS-methyl-3-phenyl-propoxy)-benzofuran-5-yl]-ethanone

To a suspension of Example 43a) (92 mg, 0.40 mmol) indichloromethane/tetrahydrofuran (1:1, 4 mL) was added polymer-boundtriphenylphosphine (1.0 mmol loading, 600 mg, 0.60 mmol),RS-4-phenylbutan-2-ol (92 μL, 0.60 mmol) and diethylazodicarboxylate (94μL, 0.60 mmol). The reaction mixture was stirred at rt for 16 h thenfiltered through a Celite pad, washing with dichloromethane andtetrahydrofuran. The solvent was concentrated in vacuo and the crudeproduct was purified by flash chromatography eluting with ethylacetate:petroleum ether (1:9, 1:4) to offer the intermediate chromenonein 73% yield. This compound was treated as described under GeneralProcedure B and the crude product was purified by flash chromatographyeluting with ethyl acetate:petroleum ether (1:9) to afford the titlecompound in 64% yield. ¹H NMR (300 MHz, CDCl₃): δ 1.34 (d, J=6.2 Hz,3H), 1.93-2.18 (m, 2H), 2.51 (s, 3H), 2.63 (s, 3H), 2.75-2.88 (m, 2H),4.74-4.80 (m, 1H), 6.73 (d, J=2.3 Hz, 1H), 7.14-7.48 (m, 5H), 7.48 (d,J=2.3 Hz, 1H), 8.74 (s, 1H).

57b)1-[4-Methyl-7-(1-RS-methyl-3-phenyl-propoxy)-6-(2-morpholin-4-yl-ethoxy)-benzofuran-5-yl]-ethanone

Example 57a) was treated with 4-(2-chloroethyl)morpholine hydrochlorideas described under General Procedure I and the crude product waspurified by flash chromatography withmethanol:ethylacetate:dichloromethane (1:29:70) to give the titlecompound in 56% yield. ¹H-NMR (300 MHz, CDCl₃) δ 1.33 (d, J=6.2 Hz, 3H),1.92-2.09 (m, 2H), 2.31 (s, 3H), 2.48-2.50 (m, 4H), 2.55 (s, 3H), 2.66(t, J=5.8 Hz, 2H), 3.67-3.70 (m, 4H), 4.12 (t, J=5.8 Hz, 2H), 4.80-4.86(m, 1H), 6.73 (d, J=2.2 Hz, 1H), 7.14-7.28 (m, 5H), 7.55 (d, J=2.2 Hz,1H).

Example 58

58a.rac-4,7-Dimethyl-9-(1S,2S-2-phenyl-cyclopropylmethoxy)-furo[3,2-g]chromen-5-one

Example 58a) was prepared by reacting Example 43a) withtrans-(2-bromomethyl-cyclopropyl)-benzene (Eur. Patent App. 445013, 4Sep. 1991) as described in General Procedure A except the reaction wasperformed at rt. The title compound was furnished in 94% yield. ¹H NMR(300 MHz, CDCl₃): δ 0.96-1.02 (m, 2H), 1.60-1.63 (m, 1H), 1.74-1.80 (m,1H), 2.23 (s, 3H), 2.96 (s, 3H), 4.22 (dd, J=10.9, 7.6 Hz, 1H), 4.48(dd, J=10.9, 6.2 Hz, 1H), 5.97 (s, 1H), 6.88-6.90 (m, 3H), 7.08-7.23 (m,3H), 7.59 (d, J=2.2 Hz, 1H). MS (ES⁺) m/z 360.9 (M+H⁺).

58b)rac-1-[6-Hydroxy-4-methyl-7-(1S,2S-2-phenyl-cyclopropylmethoxy)-benzofuran-5-yl]-ethanone

The title compound was prepared from Example 58a) as described underGeneral Procedure B in 46% yield. ¹H NMR (300 MHz, CDCl₃): δ 0.96-1.05(m, 2H), 1.54-1.62 (m, 1H), 1.82-1.88 (m, 1H), 2.51 (s, 3H), 2.60 (s,3H), 4.28-4.34 (m, 2H), 6.72 (d, J=2.2 Hz, 1H), 6.95-6.98 (m, 2H),7.09-7.23 (m, 3H), 7.47 (d, J=2.2 Hz, 1H), 9.02 (s, 1H). MS (ES⁺) m/z358.9 (M+Na⁺).

58c)1-[4-Methyl-6-(2-morpholin-4-yl-ethoxy)-7-(1S,2S-2-phenyl-cyclopropylmethoxy)-benzofuran-5-yl]-ethanone

The title compound was prepared from Example 58b) in 77% yield over twosteps in the same manner as described for Example 43e). ¹H NMR (300 MHz,CDCl₃): δ 0.99-1.04 (m, 2H), 1.58-1.65 (m, 1H), 1.85-1.91 (m, 1H), 2.30(s, 3H), 2.44-2.47 (m, 4H), 2.51 (s, 3H), 2.63 (t, J=5.6 Hz, 2H),3.66-3.69 (m, 4H), 4.13 (t, J=5.6 Hz, 2H), 4.28 (dd, J=10.5, 7.3 Hz,1H), 4.37 (dd, J=10.5, 6.6 Hz, 1H), 6.71 (d, J=2.2 Hz, 1H), 6.98-7.00(m, 2H), 7.10-7.21 (m, 3H), 7.54 (d, J=2.2 Hz, 1H). MS (ES⁺) m/z 449.9(M+H⁺).

Example 59

59a)rac-4,7-Dimethyl-9-(1S,2R-2-phenyl-cyclopropylmethoxy)-furo[3,2-g]chromen-5-one

Example 59a) was prepared by reacting Example 43a) withcis-(2-bromomethyl-cyclopropyl)-benzene (prepared bytriphenylphosphine/bromine bromination of the known alcoholprecursor—JACS, 117 (43), p 10672, 1995) as described in GeneralProcedure A except the reaction was performed at rt. The title compoundwas furnished in 64% yield. ¹H NMR (300 MHz, CDCl₃): δ 0.88-0.94 (m,1H), 1.08-1.16 (m, 1H), 1.70-1.77 (m, 1H), 2.26-2.30 (m, 1H), 2.30 (s,3H), 2.92 (s, 3H), 4.07 (dd, J=10.9, 8.0 Hz, 1H), 4.15 (dd, J=10.9, 6.6Hz, 1H), 6.00 (s, 1H), 6.87 (d, J=2.2 Hz, 1H), 7.06-7.16 (m, 5H), 7.58(d, J=2.2 Hz, 1H). MS (ES⁺) m/z 360.9 (M+H⁺).

59b)rac-1-[6-Hydroxy-4-methyl-7-(1S,2R-2-phenyl-cyclopropylmethoxy)-benzofuran-5-yl]-ethanone

The title compound was prepared from Example 59a) as described inExample 43 step iii in 46% yield. ¹H-NMR (300 MHz, CDCl₃) δ 0.94-1.00(m, 1H), 1.08-1.16 (m, 1H), 1.66-1.77 (m, 1H), 2.27-2.38 (m, 1H), 2.43(s, 3H), 2.56 (s, 3H), 3.87-3.93 (m, 1H), 4.17-4.23 (m, 1H), 6.67 (d,J=2.1 Hz, 1H), 7.16-7.29 (m, 5H), 7.43 (d, J=2.1 Hz, 1H), 7.75 (s, 1H,OH).

59c)1-[4-Methyl-6-(2-morpholin-4-yl-ethoxy)-7-(1S,2R-2-phenyl-cyclopropylmethoxy)-benzofuran-5-yl]-ethanone

The title compound was prepared from Example 59b) as described inExample 43 step iv, v in 62% yield (over 2 steps). ¹H-NMR (300 MHz,CDCl₃) δ 0.92-0.98 (m, 1H), 1.09-1.16 (m, 1H), 1.66-1.73 (m, 1H),2.27-2.37 (m, 4H), 2.42-2.52 (m, 7H), 2.60 (t, J=5.6 Hz, 2H), 3.69 (t,J=4.6 Hz, 4H), 3.92-4.15 (m, 4H), 6.67 (d, J=2.1 Hz, 1H), 7.10-7.23 (m,5H), 7.48 (d, J=2.1 Hz, 1H).

Example 60

60a) 5-Acetyl-6-hydroxy-4-methyl-7-(4-methoxybenzyloxy)benzofuran

Example 43a) was treated with 4-methoxybenzyl chloride according toGeneral Procedure A, followed by hydrolysis according to GeneralProcedure B to offer the title compound in 46% yield (over 2 steps). ¹HNMR (300 MHz, CDCl₃): δ 2.50 (s, 3H), 2.60 (s, 3H), 3.79 (s, 3H), 5.28(s, 2H), 6.73 (d, J=2.1 Hz, 1H), 6.86 (d, J=8.5 Hz, 2H), 7.36 (d, J=8.5Hz, 2H), 7.53 (d, J=2.1 Hz, 1H), 8.69 (s, 1H). MS (ES⁺) m/z 348.8(M+Na⁺).

60b)5-Acetyl-6-(2-morpholinoethoxy)-4-methyl-7-(3-phenylpropoxy)benzofuran,trifluoroacetate salt

Example 60a) was treated with 1,2-dibromoethane (4.0 eqs) according toGeneral Procedure A, followed by reaction with morpholine according toGeneral Procedure E. The corresponding morpholino derivative (439 mg,1.0 mmol) was dissolved in dichloromethane (20 mL) and cooled to 0° C.Then, anisole (5 mL) and TFA (5 mL) were added successively to thereaction mixture, which was allowed to stir at room temperatureovernight. The solvents were removed under vacuum and the crude wassonicated in 5 ml of diethyl ether:hexane (1:1) to offer thetrifluoroacetate salt as an off-white solid in 45% yield. ¹H NMR (300MHz, CDCl₃): δ 2.30 (s, 3H), 2.50 (s, 3H), 3.00-3.60 (m, 6H), J=4.7 Hz,4H), 4.18 (t, J=4.7 Hz, 2H), 6.72 (d, J=2.1 Hz, 1H), 7.62 (d, J=2.1 Hz,1H). MS (ES⁺) m/z 348.8 (M+Na⁺).

Step iv

60c)1-[4-Methyl-6-(2-morpholin-4-yl-ethoxy)-7-(3-phenyl-prop-2-ynyloxy)-benzofuran-5-yl]-ethanone

To a solution of Example 60b) (40 mg, 0.092 mmol) in dry DMF (1 mL) wasadded a solution of (3-bromopropyn-1-yl)benzene (22 mg, 0.11 mmol) inminimum DMF) and Cs₂CO₃ (60 mg, 0.18 mmol) and the resulting suspensionwas stirred at room temperature for 2 h. The reaction was quenched withwater and extracted with EtOAc. The organic layer was washed with water(×2) and brine, dried over MgSO₄ and concentrated under vacuum. Thecrude residue was purified by silica-gel flash chromatography.Yield=45%. ¹H NMR (300 MHz, CDCl₃): δ 2.33 (s, 3H), 2.55 (s, 3H),2.53-2.56 (m, 4H), 2.70-2.74 (m, 2H), 3.67-3.70 (m, 4H), 4.21 (t, J=5.6Hz, 2H), 6.75 (d, J=2.2 Hz, 1H), 7.20-7.35 (m, 5H), 7.61 (d, J=2.2 Hz,1H). MS (ES⁺) m/z 433.9 (M+H⁺).

Example 61

1-[4-Methyl-6-(2-morpholin-4-yl-ethoxy)-7-(E-3-phenyl-allyloxy)-benzofuran-5-yl]-ethanone

Example 61 was prepared from Example 60b) and((E)-3-Bromo-propenyl)benzene as described for Example 60 Step iv) in65% yield. ¹H NMR (300 MHz, CDCl₃): δ 2.31 (s, 3H), 2.47-2.50 (m, 4H),2.55 (s, 3H), 2.68 (t, J=5.6 Hz, 2H), 3.65-3.68 (m, 4H), 4.15 (t, J=5.6Hz, 2H), 5.00 (d, J=6.2 Hz, 2H), 6.47 (dt, J=15.9, 6.2 Hz, 1H), 6.72 (d,J=15.9 Hz, 1H), 6.74 (d, J=2.2 Hz, 1H), 7.21-7.39 (m, 5H), 7.60 (d,J=2.2 Hz, 1H). MS (ES⁺) m/z 435.9 (M+H⁺).

Example 62

1-[4-Methyl-6-(2-morpholin-4-yl-ethoxy)-7-(Z-3-phenyl-allyloxy)-benzofuran-5-yl]-ethanone

Example 62 was prepared from Example 60b) and((Z)-3-Bromo-propenyl)benzene as described for Example 60 Step iv) in11% yield. ¹H NMR (300 MHz, CDCl₃): δ 2.31 (s, 3H), 2.46-2.49 (m, 4H),2.54 (s, 3H), 2.64 (t, J=5.6 Hz, 2H), 3.66-3.70 (m, 4H), 4.11 (t, J=5.6Hz, 2H), 5.13 (d, J=6.4 Hz, 2H), 6.05 (dt, J=11.7, 6.4 Hz, 1H), 6.65 (d,J=11.7 Hz, 1H), 6.72 (d, J=2.2 Hz, 1H), 7.14-7.35 (m, 5H), 7.53 (d,J=2.2 Hz, 1H). MS (ES⁺) m/z 435.9 (M+H⁺).

Example 63

1-[4-Methyl-6-(2-morpholin-4-yl-ethoxy)-7-(2R,3R-3-phenyl-oxiranylmethoxy)-benzofuran-5-yl]-ethanone

The title compound was prepared from Example 60b) andtrans-2-bromomethyl-3-phenyl-oxirane (Tet Lett, 45 (46), p 8579, 2004)as described for Example 58 Step iv) except the reaction was heated to60° C. Example 63 was furnished in 53% yield. ¹H NMR (300 MHz, CDCl₃): δ2.32 (s, 3H), 2.48-2.51 (m, 4H), 2.55 (s, 3H), 2.68 (t, J=5.6 Hz, 2H),3.41-3.45 (m, 1H), 3.68-3.71 (m, 4H), 3.88 (d, J=1.9 Hz, 1H), 4.15 (t,J=5.6 Hz, 2H), 4.45 (dd, J=11.4, 5.6 Hz, 1H), 4.66 (dd, J=11.4, 3.3 Hz,1H), 6.74 (d, J=2.2 Hz, 1H), 7.22-7.37 (m, 5H), 7.57 (d, J=2.2 Hz, 1H).MS (ES⁺) m/z 451.9 (M+H⁺).

Example 64

64a) 9-(2-Bromo-ethoxy)-4,7-dimethyl-furo[3,2-g]chromen-5-one

9-(2-Bromo-ethoxy)-4,7-dimethyl-furo[3,2-g]chromen-5-one was prepared asdescribed in PCT/AU2006/000333.

64b) 4,7-Dimethyl-9-(2-phenylamino-ethoxy)-furo[3,2-g]chromen-5-one

Aniline (0.60 mmol) was added to a solution of the bromide (70 mg, 0.199mmol) in N-methylpyrrolidinone (0.5 mL) and the reaction was stirred at90° C. overnight. After cooling, water (20 mL) and CH₂Cl₂ (30 mL) wereadded and the organic layer was washed with water (20 mL) and brine (20mL), dried over MgSO₄ and concentrated under vacuum. The crude residuewas purified by flash chromatography (silica-gel, CH₂Cl₂/EtOAc, 9:1) toafford the product as a white solid (53 mg, 73%). ¹H-NMR (300 MHz,CDCl₃) δ 2.31 (s, 3H), 3.53 (t, J=4.9 Hz, 2H), 4.05 (s, 3H), 4.52 (t,J=4.8 Hz, 2H), 6.03 (s, 1H), 6.66-6.75 (m, 3H), 7.00 (dd, J=0.8, 2.2 Hz,1H), 7.19 (t, J=7.6 Hz, 2H), 7.60 (dd, J=0.8, 2.2 Hz, 1H). MS (ES⁺) m/z365.9 (M+H⁺).

64c)1-[6-Hydroxy-4-methoxy-7-(2-phenylamino-ethoxy)-benzofuran-5-yl]-ethanone

The title compound was prepared from Example 64b) as described underGeneral Procedure B in 43% yield. ¹H-NMR (300 MHz, CDCl₃) δ 2.71 (s,3H), 3.42 (t, J=5.0 Hz, 2H), 4.13 (s, 3H), 4.40 (t, J=5.1 Hz, 2H), 4.72(br s, 1H), 6.65-6.71 (m, 3H), 6.88 (d, J=2.3 Hz, 1H), 7.16 (t, J=8.4Hz, 2H), 7.47 (d, J=2.3 Hz, 1H). ¹³C NMR (75 MHz, CDCl₃) δ 205.2, 153.8,152.8, 152.0, 148.3, 143.8, 129.1, 127.1, 117.4, 113.2, 110.6, 110.4,105.9, 72.1, 60.4, 43.7, 33.2. MS (ES⁺) m/z 341.9 (M+H⁺).

64d)1-[4-Methoxy-6-(2-morpholin-4-yl-ethoxy)-7-(2-phenylamino-ethoxy)-benzofuran-5-yl]ethanone

Example 64c) was treated with 4-(2-chloroethyl)morpholine hydrochlorideas described under General Procedure I and the crude product waspurified by flash chromatography withmethanol:ethylacetate:dichloromethane (1:29:70) to give the titlecompound in 99% yield. ¹H-NMR (300 MHz, CDCl₃) δ 2.48-2.54 (m, 7H),2.66-2.70 (m, 2H), 3.47 (t, J=5.1 Hz, 2H), 3.68-3.73 (m, 4H), 3.98 (s,3H), 4.16 (t, J=5.5 Hz, 2H), 4.47 (t, J=5.1 Hz, 2H), 4.64 (br s, 1H),6.64-6.72 (m, 3H), 6.87 (d, J=2.3 Hz, 1H), 7.17 (t, J=7.4 Hz, 2H), 7.56(d, J=2.3 Hz, 1H).

Example 65

5-Acetyl-6-(2-morpholinoethoxy)-4-methyl-7-(3-phenylpropoxy)-2,3-dihydrobenzofuran

The title compound was prepared from Example 19 as described underGeneral Procedure F in 60% yield. ¹H-NMR (300 MHz, CDCl₃) δ 1.98-2.07(m, 5H), 2.46 (t J=4.2 Hz, 4H), 2.52 (s, 3H), 2.62 (t, J=5.6 Hz, 2H),2.79 (t, J=8.1 Hz, 2H), 3.07 (t, J=8.7 Hz, 2H), 3.67 (t, J=4.7 Hz, 4H),4.08 (q, J=6.5 Hz, 4H), 4.60 (t, J=8.7 Hz, 2H), 7.14-7.29 (m, 5H). MS(ES⁺) m/z 440.0 (M+H⁺).

Example 66

1-[7-[3-(4-Fluoro-phenyl)-butoxy]-4-methyl-6-(2-pyridin-2-yl-ethoxy)-2,3-dihydro-benzofuran-5-yl]-ethanone

The title compound was prepared from Example 44d) as described underGeneral Procedure F in 40% yield. ¹H-NMR (300 MHz, CDCl₃) δ 1.24 (d,J=7.0 Hz, 3H), 1.75-1.93 (m, 2H), 2.02 (s, 3H), 2.24 (s, 3H), 2.94-3.14(m, 5H), 3.84-3.93 (m, 2H), 4.35 (t, J=6.6 Hz, 2H), 4.56 (t, J=8.7 Hz,2H), 6.92 (t, J=8.7 Hz, 1H), 7.13-7.24 (m, 4H), 7.57 (dt, J=1.7 Hz, 7.6Hz, 1H), 8.51 (d, J=4.4 Hz, 1H).

Example 67

1-{6-(2-Cyclopentylamino-ethoxy)-7-[3-RS-(4-fluorophenyl)-butoxy]-4-methyl-2,3-dihydro-benzofuran-5-yl}-ethanone

The title compound was prepared from Example 45b) as described underGeneral Procedure F in 57% yield. ¹H-NMR (300 MHz, CDCl₃) δ 1.27-1.38(m, 5H), 1.50-1.49-1.72 (m, 5H), 1.78-1.86 (m, 2H), 1.92-2.04 (m, 2H),2.07 (s, 3H), 2.48 (s, 3H), 2.84 (t, J=5.3 Hz, 2H), 2.96-3.10 (m, 4H),3.92-4.01 (m, 2H), 4.08 (t, J=5.3 Hz, 2H), 4.58 (t, J=8.7 Hz, 2H),6.93-6.98 (m, 2H), 7.15-7.20 (m, 2H).

Example 68

68a) 1,3-Dimethoxy-5-methyl-2-(4-phenylbutyl)benzene

A solution of nBuLi in hexanes (1.7 M, 14 mL, 24 mmol) was added over 15min to a solution of 3,5-dimethoxytoluene (2.93 mL, 20 mmol) in THF (20mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h then atroom temperature for 3 h. The reaction was cooled to 0° C. and asolution of the 4-phenylbutylbromide (4.13 mL, 1.2 mmol) in toluene (15mL) was added over 5 min. The reaction mixture was allowed to warm toroom temperature and heated to 80° C. for 3-4 h. The reaction wasquenched slowly with water and partitioned over Et₂O (100 mL) and water(100 mL). The phases were separated and the aqueous phase was extractedwith Et₂O (3×100 mL). The pooled organics were washed with brine (120mL), dried over Na₂SO₄, and concentrated under vacuum and the crudeproduct was purified by flash chromatography (silica-gel, petroleumether/EtOAc 200:1) to afford the product as a clear oil (4.6 g, 81%). ¹HNMR (CDCl₃): δ 1.53-1.67 (m, 4H), 2.31 (s, 3H), 2.60-2.64 (m, 4H), 3.76(s, 6H), 6.34 (s, 2H), 7.13-7.22 (m, 5H).

68b) 3-Methoxy-5-methyl-2-(4-phenyl-butyl)-phenol

To a solution of NaH (60% in oil, 1.20 g, 30 mmol) in DMF (60 mL) at 0°C. was added ethanethiol (2.22 mL, 30 mmol) over 5 min. The reactionmixture was stirred at room temperature for 30 min and then a solutionof the Example 68a) (2.13 g, 7.5 mmol) in DMF (45 mL) was added. Thereaction mixture was stirred at 160° C. for 3.5 h. Upon cooling thesolution was partitioned over ethyl acetate (100 mL) and HCl_((aq)) (2M,100 mL) and the aqueous phase was extracted with ethyl acetate (2×150mL). The pooled organics were washed with brine (200 mL), dried overMgSO₄ and concentrated under vacuum. The crude product was purified byflash chromatography (silica-gel, petroleum ether/ethyl acetate, 9:1) toafford the product as a clear oil (2.2 g, 99%). ¹H NMR (CDCl₃): δ1.53-1.71 (m, 4H), 2.27 (s, 3H), 2.60-2.67 (m, 4H), 3.78 (s, 3H), 5.84(br s, 1H), 6.26 (s, 1H), 6.29 (s, 1H) 7.16-7.29 (m, 5H).

68c) 6-Methoxy-4-methyl-7-(4-phenyl-butyl)-benzofuran

To a mixture of Example 68c) (946 mg, 3.5 mmol) and K₂CO₃ (967 mg, 7.0mmol) in DMF (7 mL) was added bromoacetaldehyde diethyl acetal (1.08 mL,7.0 mmol) and the reaction mixture was stirred at 150° C. for 3.5 h.Upon cooling, further bromoacetaldehyde diethyl acetal (0.54 mL, 3.5mmol) was added and reaction mixture was stirred at 150° C. for 2.5 h,Upon cooling the reaction mixture was partitioned over ethyl acetate andwater (1:1, 200 mL) and the aqueous phase was extracted with ethylacetate (2×150 mL). The pooled organics were washed with brine (200 mL),dried over MgSO₄ and concentrated under vacuum. The crude product washeated at 50° C. under high vacuum for 3 h then purified by flashchromatography (silica-gel, petroleum ether/ethyl acetate, 100:1, 50:1)to afford the intermediate acetal (0.99 g, 73%). The acetal (0.50 g, 1.3mmol) was added to a stirred mixture of polyphosphoric acid (3.5 g) intoluene (10 mL) at 100° C. The reaction mixture was stirred at 100° C.for 3 h then cooled on an ice-bath and water (50 mL) was added. Theorganics were extracted with ethyl acetate (3×50 mL) and the pooledethyl acetate phases were washed with brine (100 mL), dried over MgSO₄and concentrated under vacuum. The crude product was purified by flashchromatography (silica-gel, petroleum ether/ethyl acetate, 200:1) toafford the title compound (0.22 g, 57%). ¹H NMR (300 MHz, CDCl₃) δ1.67-1.72 (m, 4H), 2.48 (s, 3H), 2.66 (t, J=7.2 Hz, 2H), 2.90 (t, J=7.2Hz, 2H), 3.85 (s, 3H), 6.69 (d, J=2.3 Hz, 1H), 7.16-7.28 (m, 5H), 7.53(d, J=2.3 Hz, 1H).

68d) 4,6-Dimethyl-7-(4-phenylbutyl)-benzofuran

Example 68c) (205 mg, 0.72 mmol) was treated in a similar manner asdescribed for the preparation of Example 68b) to give the title compound(199 mg, 99%) as a straw-coloured solid. ¹H NMR (300 MHz, CDCl₃) δ1.69-1.74 (m, 4H), 2.42 (s, 3H), 2.67 (m, 2H), 2.88 (m, 2H), 4.85 (br s,1H), 6.55 (s, 1H), 6.68 (d, J=2.3 Hz, 1H), 7.15-7.28 (m, 5H), 7.50 (d,J=2.3 Hz, 1H).

68e)1-[6-Hydroxy-4-methyl-7-(4-phenyl-butyl)-2,3-dihydro-benzofuran-5-yl]-ethanone

Example 68d) (150 mg, 0.53 mmol) was treated as described under GeneralProcedure F to give the intermediate dihydrofuran (136 mg, 90%). Amixture of the intermediate (64 mg, 0.20 mmol) and zinc chloride (60 mg,0.44 mmol) in ether (2.25 mL) and acetonitrile (1.75 mL) at 0° C. wastreated with HCl for 15 min. The mixture was stirred at room temperaturefor 16 h and then diluted with ether and petroleum ether, which causedan oil to separate. The reaction mixture decanted and the remaining oilwas dissolved in water (10 mL) and heated at 80° C. for 2 h. On coolingthe water was extracted with ethyl acetate (2×20 mL). The organics weredried over Na₂SO₄ and concentrated under vacuum to give the titlecompound (28 mg, 44%). ¹H NMR (300 MHz, CDCl₃) δ 1.60-1.69 (m, 4H), 2.43(s, 3H), 2.59-2.67 (m, 6H), 3.10 (t, J=8.2 Hz, 2H), 4.59 (t, J=8.2 Hz,2H), 7.12-7.28 (m, 5H), 13.80 (s, 1H).

68f)1-[4-Methyl-6-(2-morpholin-4-yl-ethoxy)-7-(4-phenyl-butyl)-2,3-dihydro-benzofuran-5-yl]-ethanone

The title compound was prepared from Example 68e) and4-(2-chloroethyl)morpholine hydrochloride as described under GeneralProcedure I in 39% yield. ¹H-NMR (300 MHz, CDCl₃) δ 1.61-1.70 (m, 4H),2.10 (s, 3H), 2.49-2.67 (m, 11H), 3.09 (t, J=8.7 Hz, 2H), 3.72-3.80 (m,6H), 4.59 (t, J=8.2 Hz, 2H), 7.16-7.29 (m, 5H).

BIOLOGICAL DATA

Potency of compounds to inhibit the human Kv1.3 ion channel weredetermined as follows:

EC50 values for inhibition of Kv1.3 currents were determined by themethod according to Schmitz et al (2005) Molecular Pharmacology 68,1254-1270 with the following differences:

-   1. Human Jurkat cells (which endogenously express hKv1.3) were used    in place of rat L929 cells.-   2. All electrophysiology was performed using planar patch clamp    (Port-A-Patch, Nanion Technologies Gmbh, Munich) in contrast to    conventional patch clamp.-   3. EC50 values shown were determined from averaged dose response    data obtained from 3 or more cells.

TABLE 1 Example No. EC₅₀ Kv1.3 microM  1 0.29  2 0.42  3 0.184  4 a)0.79  4 b) —  4 c) 0.225  5 a) —  5 b) 0.88  6 a) —  6 b) 0.72  7 0.68 8 0.75  9 2.42 10 1.51 11 0.98 12 0.69 13 b) 0.48 14 b) — 14 c) 0.91 15a) 0.27 15 b) 0.16 16 0.11 17 0.081 18 a) 0.114 18 b) 0.300 18 c) 0.4219 0.051 20 a) — 20 b) 0.068 21 a) 0.023 21 b) 0.16 22 c) 0.61 23 d)0.174 29 0.136 26 0.140 25 0.60 30 0.12 24 0.59 27 b) 0.43 28 b) 0.6431b 0.081 32 0.049 33 0.343 34 0.223 35 0.100 36 0.122 37 0.074 38 — 390.576 40 0.066 41 0.215 42 0.480 43b 0.229 43c 0.954 43e 0.286 44d 0.02245b 0.043 46b 0.198 47a 0.531 47b 0.074 48 0.047 49 — 50a 0.423 50b0.016 51 0.018 52 — 53 0.023 54a 0.16 54b 1.6 55 6.6 56b 0.362 57b 0.15958a 0.165 58b 0.512 58c 0.100 59a 0.215 59c — 60c 0.331 61 0.221 62 — 630.600 64c 0.340 64d — 65 0.200 66 0.014 67 0.008 68 0.020Effect of appending L-R₆ on Potency of Kv1.3 Inhibition

Exam- EC₅₀ ple Kv1.3 number Structure micromol 47a

0.531 47b

0.074 43c

0.954 43e

0.286 50a

0.423 50b

0.016 53

0.023 58b

0.512 58c

0.100

Throughout this specification and the claims which follow, unless thecontext requires otherwise, the word “comprise”, and variations such as“comprises” and “comprising”, will be understood to imply the inclusionof a stated integer or step or group of integers or steps but not theexclusion of any other integer or step or group of integers or steps.

The reference in this specification to any prior publication (orinformation derived from it), or to any matter which is known, is not,and should not be taken as an acknowledgment or admission or any form ofsuggestion that that prior publication (or information derived from it)or known matter forms part of the common general knowledge in the fieldof endeavour to which this specification relates.

1. A compound represented by formula (Ia) or a salt thereof,

wherein

is an optional double bond; R₁ is chloro or hydrogen; R₂ is hydrogen; R₃is methyl or methoxy; R₄ is selected from lower alkyl, lower alkoxy,C₂₋₆ alkenyl, C₂₋₆ alkenyloxy, C₂₋₆ alkynyl, or C₂₋₆ alkynyloxy, eachsubstituted by optionally substituted aryl, optionally substitutedaryloxy, optionally substituted heteroaryl, optionally substitutedheteroaryloxy, optionally substituted heterocyclyl, optionallysubstituted heterocyclyloxy, or NR′R″ (where R′ and R″ are independentlyselected from hydrogen and lower alkyl); L is a divalent linker group of1-6 atoms in length selected from optionally substituted alkylene,optionally substituted alkenylene, optionally substituted alkynylene;and R₆ is selected from halo, CN, optionally substituted C₃₋₇cycloalkyl, optionally substituted aryl, optionally substitutedheteroaryl, optionally substituted heterocyclyl, —C(O)-heterocyclyl,—C(O)NR′″R′″, —NR′″R′″, —OR′″, —S(O)R′″, —S(O)₂R′″, —Se(O)R′″, and—Se(O)₂R′″ (where each R′″ is independently selected from hydrogen,optionally substituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted C₃₋₇ cycloalkyl, optionallysubstituted heterocyclyl, optionally substituted heteroaryl, andoptionally substituted aryl).
 2. A compound of formula (Ia) or saltthereof, according to claim 1 wherein L is an optionally substitutedalkylene group.
 3. A compound of formula (Ia) or salt thereof, accordingto claim 2 wherein L is an unsubstituted alkylene group.
 4. A compoundof formula (Ia) or salt thereof, according to claim 3 wherein L is anunsubstituted ethylene, propylene, or butylene group.
 5. A compound offormula (Ia) or salt thereof, according to claim 1 wherein R₆ is CN,optionally substituted aryl, optionally substituted heteroaryl,optionally substituted heterocyclyl, —C(O)-heterocyclyl, —C(O)NR′″R′″,—NR′″R′″, —OR′″, —S(O)R′″, or —S(O)₂R′″ (where each R′″ is independentlyselected from optionally substituted alkyl, optionally substituted C₃₋₇cycloalkyl, optionally substituted heterocyclyl, optionally substitutedheteroaryl and optionally substituted aryl).
 6. A compound of formula(Ia) according to claim 1 or a salt thereof wherein

is a double bond; R₃ is methyl or methoxy; R₄ is a lower alkyl or loweralkoxy terminally substituted by aryl, aryloxy, heteroaryl,heteroaryloxy, heterocyclyl, heterocyclyloxy, or NR′R″ (where R′ and R″are independently selected from hydrogen and lower alkyl); L is adivalent linker group of 2-4 atoms in length selected from a ethylene,propylene or butylene; and R₆ is CN, optionally substituted aryl,optionally substituted heteroaryl, optionally substituted heterocyclyl,—C(O)-heterocyclyl, —C(O)NR′″R′″, —NR′″R′″, —OR′″, —SR′″, —S(O)R′″, or—S(O)₂R′″ (where R′ is selected from optionally substituted alkyl,optionally substituted C₃₋₇ cycloalkyl, optionally substitutedheterocyclyl, optionally substituted heteroaryl and optionallysubstituted aryl).
 7. A compound selected from:5-Acetyl-4,7-dimethoxy-6-(3-(phenyl)propoxy)benzofuran;5-Acetyl-4,7-dimethoxy-6-(4-(phenoxy)butoxy))benzofuran;5-Acetyl-6-(3-phenylpropoxy)benzofuran;5-Acetyl-4-methyl-7-methoxy-6-(3-(phenyl)propoxy)benzofuran;5-Acetyl-4,7-dimethoxy-6-(2-(phenoxy)ethoxy)benzofuran;5-Acetyl-4,7-dimethoxy-6-(3-(phenoxy)propoxy)benzofuran;5-Acetyl-4,7-dimethoxy-6-(2-(thiophenoxy)ethoxy)benzofuran;5-Acetyl-4,7-dimethoxy-6-(3-(phenylthio)propoxy)benzofuran;5-Acetyl-4,7-dimethoxy-6-(2-(benzenesulfonyl)ethoxy)benzofuran;5-Acetyl-4,7-dimethoxy-6-(3-(benzenesulfonyl)propoxy)benzofuran;5-Acetyl-4,7-dimethoxy-6-(2-(phenylamino)ethoxy)benzofuran;5-Acetyl-4,7-dimethoxy-6-(3-(phenylamino)propoxy)benzofuran;5-Acetyl-7-N,N-dimethylaminomethyl-4-methoxy-6-(3-(phenyl)propoxy)benzofuran;5-Acetyl-4-methoxy-7-(2-(N-morpholino)ethoxy-6-(4-(phenoxy)butoxy))benzofuran5-Acetyl-6-(2-dimethylaminoethoxy)-4-methoxy-7-(3-phenylpropoxy)benzofuran;5-Acetyl-6-(2-morpholinoethoxy)-4-methoxy-7-(3-phenylpropoxy)benzofuran;5-Acetyl-6-(2-imidazol-1-ylethoxy)-4-methoxy-7-(3-phenylpropoxy)benzofuran;5-Acetyl-6-(2-dimethylaminoethoxy)-4-methyl-7-(3-phenylpropoxy)benzofuran;5-Acetyl-6-(2-morpholinoethoxy)-4-methyl-7-(3-phenylpropoxy)benzofuran;5-Acetyl-6-(2-imidazol-1-ylethoxy)-4-methyl-7-(3-phenylpropoxy)benzofuran;5-Acetyl-6-[2-(5-aminotetrazol-2-yl)ethoxy]-4-methyl-7-(3-phenylpropoxy)benzofuran;5-Acetyl-6-[2-(5-aminotetrazol-1-yl)ethoxy]-4-methyl-7-(3-phenylpropoxy)benzofuran;5-Acetyl-6-(2-morpholin-4-yl-ethoxy)-7-(3-phenylpropoxy)benzofuran;5-Acetyl-6-(2-morpholin-4-yl-ethoxy)-4-(4-phenoxybutoxy)benzofuran;3-[6-(2-Morpholin-4-ylethoxy)-4-(4-phenoxybutoxy)benzofuran-5-yl]-3-oxo-propionicacid ethyl ester;5-Acetyl-6-(2-dimethylamino-ethoxy)-4-(4-phenoxybutoxy)benzofuran;5-Acetyl-6-(2-methyl-piperazin-1-yl)-4-methyl-7-(3-phenylpropoxy)-benzofuran;5-Acetyl-6-(3-morpholin-4-yl-propoxy)-4-methyl-7-(3-phenylpropoxy)-benzofuran;5-Acetyl-6-(4-morpholin-4-yl-butoxy)-4-methyl-7-(3-phenylpropoxy)-benzofuran;5-Acetyl-6-(3-imidazol-1-yl-propoxy)-4-methyl-7-(3-phenylpropoxy)-benzofuran;5-Acetyl-6-(4-imidazol-1-yl-butoxy)-4-methyl-7-(3-phenylpropoxy)-benzofuran;1-{4-Methyl-7-(3-phenyl-propoxy)-6-[2-(pyrazin-2-yloxy)-ethoxy]-benzofuran-5-yl}-ethanone;1-[6-(2-Cyclopentylamino-ethoxy)-4-methyl-7-(3-phenyl-propoxy)-benzofuran-5-yl]-ethanone;1-[4-Methyl-7-(3-phenyl-propoxy)-6-(2-piperidin-1-yl-ethoxy)-benzofuran-5-yl]-ethanone;1-[4-Methyl-7-(3-phenyl-propoxy)-6-(2-pyrrolidin-1-yl-ethoxy)-benzofuran-5-yl]-ethanone;1-[4-Methyl-7-(3-phenyl-propoxy)-6-(2-[1,2,3]triazol-2-yl-ethoxy)-benzofuran-5-yl]-ethanone;1-[4-Methyl-7-(3-phenyl-propoxy)-6-(2-[1,2,3]triazol-1-yl-ethoxy)-benzofuran-5-yl]-ethanone;1-[4-Methyl-7-(3-phenyl-propoxy)-6-(2-[1,2,4]triazol-1-yl-ethoxy)-benzofuran-5-yl]-ethanone;4-{2-[5-Acetyl-4-methyl-7-(3-phenyl-propoxy)-benzofuran-6-yloxy]-ethyl}-morpholin-3-one;5-Acetyl-6-(2-(2-Hydroxy-ethylamino)-ethoxy)-4-methyl-7-(3-phenylpropoxy)-benzofuran;5-Acetyl-4-methyl-7-(3-phenylpropoxy)-6-(2-pyridin-2-yl-ethoxy)benzofuran;1-[2-Chloro-4-methyl-6-(2-morpholin-4-yl-ethoxy)-7-(3-phenyl-propoxy)-benzofuran-5-yl]-ethanone;2-[5-Acetyl-4-methyl-7-(3-phenyl-propoxy)-benzofuran-6-yloxy]-1-morpholin-4-yl-ethanone;1-[7-[2-(4-Fluoro-phenoxy)-ethoxy]-4-methyl-6-(2-morpholin-4-yl-ethoxy)-benzofuran-5-yl]-ethanone;5-Acetyl-7-(3-[4-fluorophenyl]butoxy)-4-methyl-6-(2-pyridin-2-yl-ethoxy)benzofuran;5-Acetyl-7-(3-[4-fluorophenyl]butoxy)-4-methyl-6-(2-Cyclopentylamino-ethoxy)benzofuran;rac-1-[4-Methyl-7-(3-methyl-3-phenyl-butoxy)-6-(2-morpholin-4-yl-ethoxy)-benzofuran-5-yl]-ethanone,5-Acetyl-7-(3-(4-fluorophenyl)propoxy)-6-hydroxy-4-methylbenzofuran;5-Acetyl-7-(3-(4-fluorophenyl)propoxy)-4-methyl-6-(2-morpholinoethoxy)benzofuran;1-[6-(2-Cyclopentylamino-ethoxy)-4-methyl-7-(3-(4-fluoro-phenyl)-propoxy)-benzofuran-5-yl]-ethanone;1-[7-[3-(4-Fluoro-phenyl)-propoxy]-4-methyl-6-(2-pyridin-2-yl-ethoxy)-benzofuran-5-yl]-ethanone;1-[4-Methyl-6-(2-morpholin-4-yl-ethoxy)-7-(3-phenyl-butoxy)-benzofuran-5-yl]-ethanone;1-[4-Methyl-6-(2-morpholin-4-yl-ethoxy)-7-(3-phenyl-butoxy)-benzofuran-5-yl]-ethanone;rac-1-[4-Methyl-7-(3-phenyl-butoxy)-6-(2-pyridin-2-yl-ethoxy)-benzofuran-5-yl]-ethanone;1-[6-(2-Cyclopentylamino-ethoxy)-4-methyl-7-(3-phenyl-butoxy)-benzofuran-5-yl]-ethanone;5-Acetyl-6-(3-cyanopropoxy)-4-methyl-7-(3-phenylpropoxy)benzofuran;5-Acetyl-6-(3-(1H-tetrazol-5-yl)-propoxy)-4-methyl-7-(3-phenylpropoxy)benzofuran;5-Acetyl-6-(3-(1H-tetrazol-5-yl)-ethoxy)-4-methyl-7-(3-phenylpropoxy)benzofuran;5-Acetyl-7-(2,2-dimethyl-3-phenylpropoxy)-4-methyl-6-(2-morpholinoethoxy)benzofuran;1-[4-Methyl-7-(1-RS-methyl-3-phenyl-propoxy)-6-(2-morpholin-4-yl-ethoxy)-benzofuran-5-yl]-ethanone;1-[4-Methyl-6-(2-morpholin-4-yl-ethoxy)-7-(1S,2S-2-phenyl-cyclopropylmethoxy)-benzofuran-5-yl]-ethanone;1-[4-Methyl-6-(2-morpholin-4-yl-ethoxy)-7-(1S,2R,2-phenyl-cyclopropylmethoxy)-benzofuran-5-yl]-ethanone;1-[4-Methyl-6-(2-morpholin-4-yl-ethoxy)-7-(3-phenyl-prop-2-ynyloxy)-benzofuran-5-yl]-ethanone;1-[4-Methyl-6-(2-morpholin-4-yl-ethoxy)-7-(E-3-phenyl-allyloxy)-benzofuran-5-yl]-ethanone;1-[4-Methyl-6-(2-morpholin-4-yl-ethoxy)-7-(Z-3-phenyl-allyloxy)-benzofuran-5-yl]-ethanone;1-[4-Methyl-6-(2-morpholin-4-yl-ethoxy)-7-(2R,3R-3-phenyl-oxiranylmethoxy)-benzofuran-5-yl]-ethanone;1-[4-Methoxy-6-(2-morpholin-4-yl-ethoxy)-7-(2-phenylamino-ethoxy)-benzofuran-5-yl]-ethanone;5-Acetyl-6-(2-morpholinoethoxy)-4-methyl-7-(3-phenylpropoxy)-2,3-dihydrobenzofuran;1-[7-[3-(4-Fluoro-phenyl)-butoxy]-4-methyl-6-(2-pyridin-2-yl-ethoxy)-2,3-dihydro-benzofuran-5-yl]-ethanone;1-{6-(2-Cylcopentylamino-ethoxy)-7-[3-RS-(4-fluorophenyl)-butoxy]-4-methyl-2,3-dihydro-benzofuran-5-yl}-ethanone1-[4-Methyl-6-(2-morpholin-4-yl-ethoxy)-7-(4-phenyl-butyl)-2,3-dihydro-benzofuran-5-yl]-ethanone,or a salt thereof.
 8. A pharmaceutical composition comprising one ormore compounds of formula (Ia) according to claim 1 or a salt thereof,and optionally a pharmaceutically acceptable carrier or diluent.
 9. Thecompound of formula (Ia) according to claim 1 or a salt thereof whereinR₁ and R₂ are both hydrogen or R₁ is chloro and R₂ is hydrogen.